Chemical compounds

ABSTRACT

Histamine H 2  -antagonists of the formula ##STR1## wherein p is 1 or 2; R 1  is hydroxy, amino, substituted amino or a 5- to 9-membered fully saturated nitrogen-containing heterocyclic ring attached via its nitrogen atom; m is an integer of from 0 to 2; n is an integer of from 2 to 4; Z is sulfur, oxygen or methylene; and A is an optionally substituted phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl ring; and nontoxic pharmaceutically acceptable salts, hydrates, solvates or N-oxides thereof are novel anti-ulcer agents. Intermediates and processes for their preparation are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of our co-pending application Ser. No.240,034, filed Mar. 3, 1981, which is a continuation-in-part ofapplication Ser. No. 163,831, filed July 7, 1980 (and now abandoned),which is a continuation-in-part of application Ser. No. 117,182, filedJan. 31, 1980 (and now abandoned), which is a continuation-in-part ofapplication Ser. No. 72,517, filed Sept. 4, 1979 (and now abandoned).

SUMMARY OF THE INVENTION

Certain 3-(hydroxy or amino)-4-(substituted amino)- and3,4-di(substituted amino)-1,2,5-thiadiazole 1-oxides and 1,1-dioxidesare potent histamine H₂ -antagonists, inhibit gastric acid secretion andare useful in the treatment of peptic ulcers.

BACKGROUND AND PRIOR ART

Burimamide (IIa) was the first clinically effective H₂ -receptorantagonist. It inhibits gastric secretion in animals and man, but oralabsorption is poor. ##STR2## Metiamide (IIb), a subsequently evaluatedH₂ -antagonist, is more potent than burimamide and is orally active inman. Clinical utility was limited, however, owing to toxicity(agranulocytosis). Cimetidine (IIc) is as effective an H₂ -antagonist asmetiamide, without producing agranulocytosis, and has recently beenmarketed as an anti-ulcer drug.

Reviews on the development of H₂ -antagonists, including those discussedin the preceding paragraph, may be found in C. R. Ganellin, et al.,Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13(1976), and in references cited therein. Relevant patents are asfollows:

U.S. Pat. No. 4,098,898 is representative of a large number of patentsdisclosing broad classes of histamine H₂ -antagonists which areN,N'-(disubstituted)thioureas, N,N'-(disubstituted)guanidines and/orN,N'-disubstituted-1,1-diaminoethylenes in which at least one of theN-substituents is a broadly defined heterocyclylalkylthioalkyl,heterocyclylalkoxyalkyl or heterocyclylalkyl moiety. The heterocyclylring is often broadly defined as being a 5- or 6-membered N-containingheterocyclic ring which optionally contains additional hetero atomsselected from N, S and O, and which is optionally substituted. U.S. Pat.No. 4,098,898 discloses compounds of the formula ##STR3## wherein X issulfur, CHNO₂, NCN or NH; Y is amino, (lower)alkylamino,di(lower)alkylamino, (lower)alkoxy, phenylethyl, imidazolylethyl, allyl,2,2,2-trifluoroethyl or (CH₂)_(n) R; Z is sulfur or methylene; Het is animidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, triazoleor thiadiazole ring which is optionally substituted by (lower)alkyl,hydroxy, halogen or amino; n is 1-12; and R is hydroxy, (lower)alkoxy,amino or (lower)alkylamino; provided that when X is NH, Y is2,2,2-trifluoroethyl or (CH₂)_(n) R and that when X is NCN, Y is notamino or (lower)alkylamino.

U.S. Pat. No. 4,062,863 discloses histamine H₂ -antagonists of theformula ##STR4## wherein R is hydrogen, (lower)alkyl or --(CH₂)₂ Z'CH₂Het'; Z and Z' each are sulfur or methylene; and Het and Het' each arean imidazole ring optionally substituted by methyl or bromo, a pyridinering optionally substituted by hydroxy, methoxy, chloro or bromo, athiazole ring or an isothiazole ring; and pharmaceutically acceptableacid addition salts thereof. U.S. Pat. Nos. 4,120,968 and 4,120,973 arerelated cases having substantially identical disclosures.

U.S. Pat. No. 4,104,381 discloses histamine H₂ -antagonists of theformula ##STR5## wherein Het is a nitrogen-containing heterocycle suchas imidazole, pyridine, thiazole, isothiazole or thiadiazole which isoptionally substituted by (lower)alkyl, amino, hydroxy or halogen; Z issulfur or methylene; n is 2 or 3; and A, taken together with thenitrogen and carbon atoms to which it is attached, forms a pyrimidine,imidazoline, quinazoline, pyridine, benzothiadiazine, 1,2,4-thiadiazine,thiazoline, 1,2,4-triazine or quinoline ring, said ring having a keto,thione or sulfone group and being optionally substituted by one or two(lower)alkyl, phenyl or benzyl groups; and pharmaceutically acceptableacid addition salts thereof. This patent includes within its scope, andstates to be one of four "particularly important" classes, substituted1,2,4-thiadiazine compounds of the formula ##STR6## wherein Het is asdefined above, Z is sulfur or methylene, and Y¹ and Y² are independentlyhydrogen, (lower)alkyl, phenyl or benzyl, or Y¹ and Y², taken togetherwith the adjacent carbon atoms, may form a fused phenyl ring. U.S. Pat.Nos. 3,932,644, 4,005,205, 4,035,374 and 4,153,793 are related caseshaving substantially the same disclosure.

Belgian Pat. No. 864,992 discloses compounds which are simultaneouslyhistamine H₁ -antagonists and histamine H₂ -antagonists having theformula ##STR7## wherein Het' is a 2- or 4-benzimidazolyl ring which isoptionally substituted by (lower)alkyl, halogen, CF₃ or CH₂ OH, a2-pyridyl ring which is optionally substituted by 1 or 2 (lower)alkyl,(lower)alkoxy, halogen, amino or OH groups, a 2-pyridyl ring condensedwith a phenyl group or with a cyclic ether containing 2 oxygen atoms, a2-thiazolyl ring, a 3-isothiazolyl ring which is optionally substitutedby Cl or Br, a 1,2,5-thiadiazol-3-yl ring which is optionallysubstituted by Cl or Br, or a 5-amino-1,3,4-thiadiazol-2-yl ring; Z' isCH₂ or S; x is 1-5; Y is 1- or 2-naphthyl,2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, phenyl substituted byone or more alkyl, (lower)alkoxy, halogen, aralkoxy, OH, alkoxyalkoxy,CF₃, di(lower)alkylamino, phenoxy, halophenoxy, alkoxyphenoxy, phenyl,halophenyl or alkoxyphenyl groups, or Y is a 5- or 6-memberedheterocyclyl ring which is optionally substituted by a (lower)alkyl or(lower)alkoxy group, and optionally has a fused benzene ring; and when xis 2-5, Y may also be phenyl.

U.S. Pat. No. 4,128,658 discloses histamine H₂ -antagonists of theformula ##STR8## wherein R₁ and R₂ are hydrogen, (lower)alkyl,cycloalkyl, (lower)alkenyl, aralkyl or (lower)alkyl interrupted by anoxygen atom or the group --N(R₄)-- in which R₄ is hydrogen or(lower)alkyl, or R₁ and R₂ taken together with the N atom to which theyare attached may form a heterocyclic ring optionally containing otherheteroatoms selected from O and --N(R₄)--; R₃ is hydrogen, (lower)alkyl,(lower)alkenyl or alkoxyalkyl; X is --CH₂ --, O or S; Y is S, O, NR₅ orCHR₆ ; Alk is a straight or branched alkylene chain of 1 to 6 carbonatoms; R₅ is H, NO₂, CN, (lower) alkyl, aryl, alkylsulfonyl orarylsulfonyl; R₆ is NO₂, arylsulfonyl or alkylsulfonyl; m is an integerof from 2 to 4; n is 1 or 2, or, when X is S or CH₂, n is 0, 1 or 2; andphysiologically acceptable salts, hydrates and N-oxides thereof. Thedisclosure of U.K. Published Application No. 2,006,771 is substantiallythe same as U.S. Pat. No. 4,128,658 except that X may not be methylene,and the furan ring has a substituent adjacent the dialkylaminoalkylgroup which is selected from (lower)alkyl, (lower)alkoxy(lower)alkyl,hydroxy(lower)alkyl, (lower)alkoxycarbonyl,(lower)alkylthio(lower)alkyl, halogen and aryl.

The disclosure of Belgian Pat. No. 867,106 is similar to that of U.S.Pat. No. 4,128,658, except that the disubstituted furyl ring is replacedby a similarly disubstituted phenyl ring.

The disclosure of Belgian Pat. No. 867,105 is similar to that of U.S.Pat. No. 4,128,658 except that the disubstituted furyl ring is replacedby a similarly disubstituted thienyl ring.

U.K. Published Patent Application No. 2,001,624 discloses histamine H₂-antagonists of the formula ##STR9## wherein X is S or NH; Y is O, S,SO, CH₂, a direct bond or a vinylene radical; m is 0 to 4; n is 1 to 4;R¹ is H, halogen or alkyl; R² is hydrogen, alkyl, alkanoyl or aroyl; Ais a 3,4-dioxocyclobuten-1,2-diyl radical or C═Z in which Z is O, S,NCN, NNO₂, CHNO₂, NCONH₂, C(CN)₂, NCOR³, NCO₂ R³, NSO₂ R³ or NR⁴ inwhich R³ is alkyl or aryl and R⁴ is hydrogen or alkyl; B is alkoxy,alkylthio or NR⁵ R⁶ in which R⁵ and R⁶ are independently hydrogen,alkyl, alkenyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkylor dialkylaminoalkyl; and salts thereof.

Belgian Pat. No. 866,155 discloses histamine H₂ -antagonists of theformula ##STR10## wherein R¹ is H or (lower)alkyl; Y is S or CH₂ ; and Zis S or NCN; and pharmaceutically acceptable acid addition saltsthereof.

U.S. Pat. No. 4,112,234 discloses histamine H₂ -antagonists of theformula ##STR11## wherein R¹ is a straight or branched chain alkynylgroup containing from 3 to 9 carbon atoms; and nontoxic pharmaceuticallyacceptable salts thereof.

U.S. Pat. No. 4,145,546 discloses compounds which are simultaneouslyhistamine H₁ -antagonists and histamine H₂ -antagonists, having theformula ##STR12## wherein Het' is a 2- or 4-imidazolyl ring optionallysubstituted by (lower)alkyl, halogen, trifluoromethyl or hydroxymethyl,a 2-pyridyl ring optionally substituted by (lower)alkyl, (lower)alkoxy,halogen, amino or hydroxy, a 2-pyridyl ring which is disubstituted by(lower)alkoxy groups or which has a phenyl, carbocyclic or cyclic etherring containing two oxygen atoms fused to it, a 2-thiazolyl ring, a3-thiazolyl ring optionally substituted by chlorine or bromine, a3-(1,2,5-thiadiazolyl) ring optionally substituted by chlorine orbromine, or a 2-(5-amino-1,3,4-thiadiazolyl) ring; Z is sulfur ormethylene; X is oxygen or sulfur; W is methylene, oxygen or sulfur; mand n are such that their sum is from 1 to 4 when W is oxygen or sulfur,or from 0 to 4 when W is methylene; A is a 1- or 2-naphthyl ring, a2,3-dihydro-1,4-benzodioxinyl ring, a 1,3-benzodioxolyl ring or a phenylring substituted by one or more (lower)alkyl, (lower)alkoxy, halogen,arylalkoxy, hydroxy, (lower)alkoxy(lower)alkoxy, trifluoromethyl,di(lower)alkylamino, phenoxy, halophenoxy, (lower)alkoxyphenoxy, phenyl,halophenyl or (lower)alkoxyphenyl groups; and when --(CH₂)_(m)W(CH₂)_(n) -- is not a methylene group, A may also be phenyl; and Y³ ishydrogen or (lower)alkyl; and acid addition salts thereof. Thedisclosure of U.S. Pat. No. 4,159,329 is substantially the same as thatof U.S. Pat. No. 4,145,546. The disclosure of U.S. Pat. No. 4,154,834 issubstantially the same as that of U.S. Pat. No. 4,145,546, except that Ais a 5- or 6-membered heterocyclic ring selected from pyridine,pyridine-N-oxide, furan, thiophene, thiazole, oxazole, isothiazole,imidazole, pyrimidine, pyrazine, pyridazine and thiadiazole, which areoptionally substituted by 1 or 2 (lower)alkyl, (lower)alkoxy, halogen,hydroxy or amino groups, or A is a pyridine ring with a carbocyclic orcyclic ether ring containing two oxygen atoms fused to it; or A is apyridine, imidazole or thiazole ring having a benzene ring fused to it.

U.K. Published Patent Application Ser. No. 2,023,133 discloses histamineH₂ -antagonists of the formula ##STR13## wherein R₁ and R₂ areindependently hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl,trifluoroalkyl or alkyl substituted by hydroxy, alkoxy, amino,alkylamino, dialkylamino or cycloalkyl, or R₁ and R₂, taken togetherwith the nitrogen to which they are attached, may be a 5 to 10-memberedalicyclic heterocyclic ring which may be saturated or may contain atleast one double bond, which may be substituted by one or more alkylgroups or a hydroxy group and/or which may contain another heteroatom;Alk is a straight or branched alkylene chain of 1-6 carbon atoms; Q is afuran or thiophene ring incorporated into the molecule via the 2- and5-positions, the furan ring optionally bearing a further substituent R₇adjacent the R₁ R₂ N-Alk-group, or Q is a benzene ring incorporated intothe molecule via its 1- and 3- or 1- and 4-positions; R₇ is halogen,alkyl (which may be substituted by hydroxy or alkoxy); X is methylene,oxygen, sulfur or >N-R⁶ in which R.sup. 6 is hydrogen or methyl; n is 0,1 or 2; m is 2, 3 or 4; R₃ is hydrogen, alkyl, alkenyl, aralkyl,hydroxyalkyl having at least two carbon atoms, alkoxyalkyl or aryl; andR₄ and R₅ are independently hydrogen, alkyl, alkyl substituted byhydroxy or C₁₋₃ alkoxy, alkenyl, aralkyl or heteroaralkyl, or R₄ and R₅taken together with the nitrogen to which they are attached, may be a 5to 7-membered saturated heterocyclic ring which may contain anotherheteroatom or the group >NR⁶, or R₄ and R₅ taken together may be thegroup >CR₈ R₉ wherein R₈ is aryl or heteroaryl and R₉ is hydrogen oralkyl; and physiologically acceptable salts and hydrates thereof.

Although the three other isomeric thiadiazoles (the 1,2,3-, 1,2,4- and1,3,4-isomers) were known previously, 1,2,5-thiadiazole was firstprepared in 1958. Since that time a large number of 3-substituted- and3,4-disubstituted-1,2,5-thiadiazoles have been reported in theliterature, including a small number of simple 3,4-di(substitutedamino)-1,2,5-thiadiazoles, e.g. the 3,4-bis(dimethylamino) compound.See, for example the review in Advances in Heterocyclic Chemistry, A. R.Katritzky and A. J. Boulton, Eds., 9, 107-163, Academic Press, New York(1968) and the publications in J. Het. Chem., 13, 13 (1976) and J. Med.Chem., 15, 315 (1972). A moderate number of3,4-disubstituted-1,2,5-thiadiazole 1,1-dioxides are known, includingthe 3,4-dichloro-, 3,4-dimethoxy- and 3,4-diethoxy useful as startingmaterials for the preparation of compounds of Formula I in which p is 2.3,4-Diamino- and a small number of simple 3,4-di(substitutedamino)-1,2,5-thiadiazole 1,1-dioxides are known, e.g. thebis(methylamino)-, bis(dimethylamino)- and bis(o-carboxyphenylamino)-compounds. See, for example, the above-cited review article and J. Org.Chem., 40, 2743 (1975). Similar derivatives of 1,2,5-thiadiazole 1-oxidehave not been reported. Certain 3-hydroxy-4-(substituted amino)derivatives of 1,2,5-thiadiazoles are known. For example, J. Org. Chem.,41, 3121 (1976) reports the synthesis of3-hydroxy-4-(N-morpholino)-1,2,5-thiadiazole and J. Org. Chem., 40, 2743(1975) reports the preparation of3-hydroxy-4-(N-piperidino)-1,2,5-thiadiazole 1,1-dioxide.Correspondingly substituted 1,2,5-thiadiazole 1-oxides apparently arenot known. To our knowledge, the only reported disubstituted1,2,5-thiadiazole 1-oxide is the 3,4-dihydroxy compound. None of the3,4disubstituted-1,2,5-thiadiazole derivatives of the present inventionare known. None of the above-cited known3,4-disubstituted-1,2,5-thiadiazole derivatives have been reported tohave H₂ -antagonist or anti-ulcer activity.

Complete Disclosure

This application relates to histamine H₂ -antagonists which areeffective inhibitors of gastric acid secretion in animals, includingman, which are useful in the treatment of peptic ulcer disease, andwhich have the formula ##STR14## wherein p is 1 or 2;

R¹ is hydroxy or NR² R³ ;

R² and R³ each are independently hydrogen, (lower)alkyl, (lower)alkenyl,(lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower)alkyl,(lower)alkoxy(lower)alkyl, (lower)alkylthio(lower)alkyl, 2-fluoroethyl,2,2,2-trifluoroethyl or cyano(lower)alkyl, or, when R² is hydrogen, R³may also be cyclo(lower)alkyl, amino(lower)alkyl,(lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl,pyrrolidino(lower)alkyl, piperidino(lower)alkyl, morpholino(lower)alkyl,piperazino(lower)alkyl, pyridyl(lower)alkyl, substitutedpyridyl(lower)alkyl wherein the pyridyl ring may contain one substituentselected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen,amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)alkoxy,2,3-dihydroxypropyl, cyano, amidino, (lower)alkylamidino, A'--(CH₂)_(m')Z'(CH₂)_(n') --, phenyl, phenyl(lower)alkyl, substituted phenyl orsubstituted phenyl(lower)alkyl, wherein the phenyl ring may contain oneor two substituents independently selected from (lower)alkyl, hydroxy,(lower)alkoxy and halogen or one substituent selected frommethylenedioxy, trifluoromethyl and di(lower)alkylamino; or R² and R³,taken together, may be --CH₂ CH₂ X(CH₂)_(r) --;

r is an integer of from 1 to 3, inclusive;

X is methylene, sulfur, oxygen or N-R⁴, provided that, when r is 1, X ismethylene;

R⁴ is hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl,(lower)alkanoyl or benzoyl;

m and m' each are independently an integer of from zero to 2, inclusive;

n and n' each are independently an integer of from 2 to 4, inclusive;

Z and Z' each are independently sulfur, oxygen or methylene;

A and A' each are independently phenyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A'independently may contain one or two substituents, the first substituentbeing selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen,amino, hydroxymethyl, (lower)alkoxy, ##STR15## and the secondsubstituent being selected from (lower)alkyl, hydroxy, trifluoromethyl,halogen, amino, hydroxymethyl and (lower)alkoxy;

q is an integer of from 0 to 6, inclusive; R¹⁴ and R¹⁵ independently arehydrogen or (lower)alkyl, or, if R¹⁴ is hydrogen, R¹⁵ also may be(lower)alkanoyl or benzoyl, or R¹⁴ and R¹⁵, taken together, may beethylene; and

R⁵ and R⁶ each are independently hydrogen, (lower)alkyl, (lower)alkenyl,(lower)alkynyl, (lower)alkoxy(lower)alkyl, cyclo(lower)alkyl, phenyl orphenyl(lower)alkyl, provided that R⁵ and R⁶ may not both becyclo(lower)alkyl or phenyl; or R⁵ and R⁶, taken together with thenitrogen atom to which they are attached, may be pyrrolidino,methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino,piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino,N-methylpiperazino, homopiperidino, heptamethyleneimino oroctamethyleneimino;

or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate orN-oxide thereof.

This application also relates to processes for the preparation of thecompounds of Formula I and to intermediates in the preparation ofcompounds of Formula I.

The present invention includes within its scope all possible tautomericforms, geometric isomers, optical isomers and zwitterionic forms of thecompounds of Formula I as well as mixtures thereof. As used herein andin the claims, the terms "(lower)alkyl," "(lower)alkenyl,""(lower)alkynyl," "(lower)alkoxy" and "(lower)alkylthio" mean, in theirbroadest sense, straight or branched chain alkyl, alkenyl, alkynyl,alkoxy and alkylthio groups containing from 1 to 12 carbon atoms.Preferably, these groups contain from 1 to 8 carbon atoms and, mostpreferably, from 1 to 6 carbon atoms. The term "nontoxicpharmaceutically acceptable salts" includes not only acid additionsalts, but also alkali metal and alkaline earth metal salts. Compoundsof Formula I have been found to form metallic salts such as potassium,sodium and calcium salts. It is believed that these salts are formed bydisplacement of a proton from the hydroxy group (when R¹ is hydroxy) orfrom one of the nitrogen atoms adjacent the thiadiazole ring, but thisis only theory and in no way limits the invention thereto.

In the compounds of Formula I, A and A', independently, are preferablyoptionally substituted phenyl, imidazolyl, thiazolyl, oxazolyl,thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl rings. Mostpreferably, A and A', independently, are optionally substituted phenyl,imidazolyl, thiazolyl, furyl, thienyl or pyridyl rings. Particularlypreferred A and A' groups are guanidino-substituted thiazolyl,di(lower)alkylamino(lower)alkyl-substituted (and especiallydimethylaminomethyl-substituted) furyl,di(lower)alkylamino(lower)alkyl-substituted (and especiallydimethylaminomethyl-substituted) thiazolyl,di(lower)alkylamino(lower)alkyl-substituted (and especiallydimethylaminomethyl-substituted) phenyl, guanidino-substituted phenyl,cycloalkyleneimino(lower)alkyl-substituted (and especiallycycloalkyleneiminomethyl-substituted) phenyl anddi(lower)alkylamino(lower)alkyl-substituted (and especiallydimethylaminomethyl-substituted) thienyl moieties.

It is preferred that m is zero or 1 and n is 2 or 3. Preferably, X issulfur, oxygen or methylene (and most preferably sulfur or oxygen). R¹preferably is NR² R³ in which R² and R³ preferably are eachindependently selected from hydrogen, (lower)alkyl, (lower)alkenyl,(lower)alkynyl, pyridyl(lower)alkyl or A'--(CH₂)_(m') Z'(CH₂)_(n') --.In particularly preferred embodiments, R² is hydrogen and R³ ishydrogen, (lower)alkyl (especially methyl, ethyl or propyl),(lower)alkenyl (especially 2-propenyl), (lower)alkynyl (especially2-propynyl), pyridyl(lower)alkyl or A'--(CH₂)_(m') Z'(CH₂)_(n') -- inwhich m' is preferably zero or 1, n' is preferably 2 or 3, Z' ispreferably sulfur or oxygen, and A' is preferably a substitutedthiazolyl, phenyl or furyl ring (and especially guanidino-substitutedthiazolyl, dimethylaminomethyl-substituted phenyl,dimethylaminomethyl-substituted furyl or guanidino-substituted phenyl).

The compounds of Formula I may be prepared by various procedures,preferably starting from a compound of the formula ##STR16## in which R⁷is a good leaving group such as halogen, phenoxy, substituted phenoxy,phenylthio, substituted phenylthio, alkoxy, alkylthio, and the like.Suitable leaving groups are well known to those skilled in the art.Preferably, R⁷ is (lower)alkoxy (especially methoxy).

Preparation of Starting Materials

Starting materials of Formula II in which p is 2 and each R⁷ is chloro,methoxy or ethoxy are known, their preparation being described in J.Org. Chem. 40, 2743 (1975). Starting materials of Formula II in which pis 2 and each R⁷ is alkoxy, alkylthio, phenoxy, phenylthio, substitutedphenoxy or substituted phenylthio (compounds of Formula IV and V) may beprepared by reacting the dichloro compound of Formula III with theappropriate alkanol, alkylthiol, phenol, thiophenol, substituted phenolor substituted thiophenol to produce the corresponding compound ofFormula IV or V in which R⁸ is alkyl, phenyl or substituted phenyl, asfollows: ##STR17## The reaction is conducted in an inert organic solventsuch as ether, dimethylformamide, or the like. When reactant R⁸ OH or R⁸SH is a liquid, e.g. methanol, ethanol, ethylmercaptan or thiophenol,the reaction may be conducted in an excess of that reactant as asolvent. Corresponding starting materials of Formula II in which p is 1(compounds of Formula VII and VIII) may be prepared in the same mannerfrom a compound of Formula II in which each R⁷ is chloro (compound VI).##STR18## Compound VI is a novel compound but it may be prepared fromthe known compound 3,4-dihydroxy-1,2,5-thiadiazole 1-oxide [itselfprepared according to the procedure of Org. Prep. Proced., 1, 255(1969)] by the same procedure utilized for preparing the compound ofFormula III from 3,4-dihydroxy-1,2,5-thiadiazole 1,1-dioxide [see J.Org. Chem., 40, 2743 (1975)]. The starting materials of Formulae VII andVIII are novel compounds not previously described in the literature.

Alternatively, the starting materials of Formulae IV and VII may beprepared by reaction of an appropriately substituted oxaldiimidate esterof Formula IX with SCl₂ or S₂ Cl₂ in an inert solvent such asdimethylformamide to form the correspondingly 3,4-disubstituted1,2,5-thiadiazole of Formula X which is then oxidized to thecorresponding 1-oxide of Formula VII or 1,1-dioxide of Formula IV.##STR19## Oxaldiimidate esters of Formula IX in which R⁸ is methyl,ethyl, n-propyl, isopropyl, n-butyl and n-pentyl are known and theirpreparation is described in Chem. Ber., 107, 3121 (1974). Correspondingcompounds in which R⁸ is phenyl, optionally substituted by (lower)alkyl,(lower)alkoxy, halogen or nitro may be prepared by a similar procedure.Compounds of Formula X in which R⁸ is methyl or ethyl are described inJ. Org. Chem., 40, 2749 (1975).

The literature reports that the 1,2,5-thiadiazole nucleus is sensitiveto oxidation, that oxidation of thiadiazoles with peracids is usuallyaccompanied by ring destruction and formation of sulfate ion, and thatattempts to prepare 1,2,5-thiadiazole 1,1-dioxide by peracetic acidoxidation of the parent ring resulted in ring cleavage. Surprisingly, wehave found that the 3,4-disubstituted-1,2,5-thiadiazole 1-oxides ofFormula VII and 1,1-dioxides of Formula IV may readily be prepared ingood yield by oxidation of the correspondingly3,4-disubstituted-1,2,5-thiadiazole of Formula X with a peracid such asm-chloroperbenzoic acid, in an inert solvent such as chloroform. Thepreparation of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide is shown inExample 4, Step A; the preparation of the corresponding 1,1-dioxide isshown below.

Illustrative Procedure No. 1 3,4-Dimethoxy-1,2,5-thiadiazole 1,1-dioxide

A solution of 3,4-dimethoxy-1,2,5-thiadiazole (1.48 g; 10.1 mmoles)[prepared according to the procedure described in J. Org. Chem., 40,2749 (1975)] in 20 ml of chloroform was added over a period of 1 minuteto a stirred solution of m-chloroperbenzoic acid (4.11 g; 20.3 mmoles;85% assay) in 60 ml of chloroform. After stirring at ambient temperaturefor 1 hour, the mixture was heated at reflux temperature for 8 hours andthen stirred at ambient temperature for 1 hour. The reaction mixture wasextracted with aqueous sodium bicarbonate and water, and the organicphase was dried over sodium sulfate, filtered and evaporated underreduced pressure. The residue was treated with methanol and filtered togive 1.03 g of product. Recrystallization from methanol yielded thetitle compound, mp 200°-202°.

Anal. Calcd. for C₄ H₆ N₂ O₄ S: C, 26.97; H, 3.39; N, 15.72; S, 18.00.Found: C, 26.82; H, 3.18; N, 16.09; S, 18.00.

We have now found a particularly elegant procedure by which a compoundof Formula VII may be prepared in a one-step reaction directly from acompound of Formula IX, by reaction of the latter with thionyl chloride.This ##STR20## reaction is conducted in an inert organic solvent such asmethylene chloride, chloroform, or the like. Although the reaction maybe conducted without the addition of a base as an acid scavenger, weprefer to add about two equivalents of a base to remove the HCl which isformed is the reaction. Higher yields of Compound VII are therebyobtained. Suitable bases include inorganic bases such as sodiumcarbonate, potassium carbonate, sodium bicarbonate and potassiumbicarbonate, and organic bases such as triethylamine, pyridine and thelike. This process not only eliminates one step, but is much moreeconomical in that it avoids the use of expensive oxidizing agents suchas m-chloroperbenzoic acid. The reaction may be conducted at atemperature of from about -20° to about 25°, and preferably at about 0°to about 10°. Illustrative Procedure No. 2 shows the preparation, bythis process, of the compound of Formula VII in which R⁸ is methyl.

Illustrative Procedure No. 2 3,4-Dimethoxy-1,2,5-thiadiazole 1-oxide

A solution of dimethyl oxaldiimidate (4.0 gm; 34.5 mmole) and pyridine(5.71 ml, 5.58 gm; 70.6 mmole) in 8 ml of CH₂ Cl₂ was added dropwise toa cold solution of thionyl chloride (2.61 ml, 4.25 gm; 34.7 mmole) in 18ml of CH₂ Cl₂ under a stream of nitrogen, at such a rate that thereaction temperature remained between 0° and 15°. After stirring atambient temperature for 20 minutes, the reaction mixture was washed withtwo 11 ml portions of aqueous 0.055 N HCl. The aqueous phase wasextracted with two 20 ml portions of CH₂ Cl₂ and the combined organicphase was dried and evaporated to dryness under reduced pressure. Thesolid residue was recrystallized from isopropyl alcohol to give 3.0 gmof the title compound, mp 137°-139°.

The compounds of Formula I may be prepared from a compound of Formula IIby various alternative reaction schemes via several classes of novelintermediates. ##STR21##

In reaction Scheme 1, R⁹ may be --NR² R³ or --NH(CH₂)_(n') Z'(CH₂)_(m')A'. When A', Z', m' and n' are the same as A, Z, m and n, the reactionmay, of course, be carried out in one step by reacting the compound ofFormula II with two equivalents of A(CH₂)_(m) Z(CH₂)_(n) NH₂. Theintermediates of Formula XI are all novel. The intermediates of FormulaXII are novel except for the compound in which p is 2, R⁷ is methoxy andR⁹ is morpholino, that compound having been described in J. Org. Chem.,40, 2743 (1975). The reactions are conducted in an inert organicsolvent; we find methanol to be a convenient and readily availablesolvent. The reaction temperature is not critical. Most startingmaterials are quite reactive and we prefer to conduct the reaction at atemperature below room temperature, e.g. 0°-10°. With some less reactivecompounds it is convenient to conduct the reaction at room temperature.Sometimes it is desirable to subsequently raise the temperature of thereaction mixture (e.g. to 50°-60° C.) to complete the reaction.##STR22##

In Reaction Scheme 2, M is a metal cation which is preferably K⁺, Li⁺ orNa⁺. The reaction conditions and solvents are as described for ReactionScheme 1. All intermediates of Formula XI are novel compounds. ##STR23##

In Reaction Scheme 3, R¹⁰ is --NR² R³ or --NH(CH₂)_(n') Z'(CH₂)_(m') A',and X is a conventional leaving group. Suitable leaving groups include,for example, fluoro, chloro, bromo, iodo, --O₃ SR¹¹ in which R¹¹ is(lower)alkyl [e.g. methanesulfonate], aryl or substituted aryl [e.g.benzenesulfonate, p-bromobenzenesulfonate or p-toluenesulfonate], O₃ SF,acetoxy and 2,4-dinitrophenoxy. For convenience and economy we prefer toutilize a compound in which X is chloro. The reaction conditions for thepreparation of the compounds of Formulae XIII, XIV and XV are asdescribed for Reaction Scheme 1. The reaction of the compound of FormulaXV with A(CH₂)_(m) X may be conducted in any inert organic solvent suchas an alkanol, acetonitrile, dimethylformamide, dimethylsulfoxide,acetone, or the like. We prefer to conduct the reaction in an alkanolsuch as methanol, ethanol or isopropanol. The reaction temperature isnot critical; the reaction may be conducted at temperatures of fromabout 0° to about 200° C. At low temperatures the reaction is slow,while high temperatures normally lead to less pure products due todecomposition and the formation of side-products. We normally prefer toconduct the reaction at room temperature. The reaction of the compoundof Formula XV with A(CH₂)_(m) X to produce the compound of Formula Icpreferably is conducted in the presence of a base, which facilitates thereaction by acting as an acid acceptor. Suitable bases include, forexample, NaOH, KOH, LiOH, triethylamine, dimethylaniline, sodiumethoxide and the like. Where X is hydroxyl, the reaction may beconducted in concentrated mineral acid, e.g. HCl (see Example 25). Allintermediates of Formula XIII, XIV and XV are novel compounds.

In a preferred embodiment of the invention the compounds of Formula Ihave the structure ##STR24## wherein p is 1 or 2;

R² and R³ each are independently hydrogen, (lower)alkyl, (lower)alkenyl,(lower)alkynyl or cyclo(lower)alkyl(lower)alkyl, or, when R² ishydrogen, R³ also may be pyridyl(lower)alkyl, substitutedpyridyl(lower)alkyl wherein the pyridyl ring may contain one substituentselected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen,A'--(CH₂)_(m') Z'(CH₂)_(n') --, phenyl(lower)alkyl or3,4-methylenedioxybenzyl;

m and m' each are independently zero or 1;

n and n' each are independently 2 or 3;

Z and Z' each are independently sulfur, oxygen or methylene;

A and A' each are independently phenyl, imidazolyl, thiazolyl, furyl,thienyl or pyridyl; provided that A and A' independently may contain oneor two substituents, the first substituent being selected from(lower)alkyl, ##STR25## and the second substituent being selected from(lower)alkyl; R¹⁴ and R¹⁵ independently are hydrogen or (lower)alkyl, orR¹⁴ and R¹⁵, taken together, may be ethylene; and

R⁵ and R⁶ each are independently hydrogen or (lower)alkyl; or R⁵ and R⁶,taken together with the nitrogen atom to which they are attached, may bepyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino,thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino,hydroxypiperidino, N-methylpiperazino, homopiperidino,heptamethyleneimino or octamethyleneimino;

or a nontoxic, pharmaceutically acceptable salt, hydrate, solvate orN-oxide thereof.

In another preferred embodiment of the invention the compounds ofFormula I have the structure ##STR26## wherein p is 1 or 2; Z is sulfuror methylene; R² and R³ each are independently hydrogen or (lower)alkyl,or, when R² is hydrogen, R³ also may be (lower)alkenyl, (lower)alkynyl,phenyl(lower)alkyl, cyclo(lower)alkyl(lower)alkyl, pyridylmethyl or##STR27## R¹⁶ is methyl and R¹³ is hydrogen or methyl, or R¹⁶ and R¹³,taken together with the nitrogen atom to which they are attached, may bepiperidino; or a nontoxic pharmaceutically acceptable salt, hydrate,solvate or N-oxide thereof.

In another preferred embodiment of the invention the compounds ofFormula I have the structure ##STR28## wherein p is 1 or 2; Z is sulfuror methylene; R¹⁴ and R¹⁵ independently are hydrogen or methyl, or, R¹⁴and R¹⁵, taken together, may be ethylene; and R² and R³ each areindependently hydrogen or (lower)alkyl, or, when R² is hydrogen, R³ alsomay be (lower)alkenyl, (lower)alkynyl, pyridylmethyl, ##STR29## or anontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof.

In another preferred embodiment of the invention the compounds ofFormula I have the structure ##STR30## wherein p is 1 or 2; Z is sulfuror methylene; R² and R³ each are independently hydrogen or (lower)alkyl,or when R² is hydrogen, R³ also may be (lower)alkenyl, (lower)alkynyl or##STR31## and R¹³ is hydrogen or methyl; or a nontoxic pharmaceuticallyacceptable salt, hydrate, solvate or N-oxide thereof.

In another preferred embodiment of the invention the compounds ofFormula I have the structure ##STR32## wherein p is 1 or 2; Z is sulfuror methylene; R² and R³ each are independently hydrogen or (lower)alkyl,or, when R² is hydrogen, R³ also may be (lower)alkenyl, (lower)alkynyl,phenyl(lower)alkyl, pyridylmethyl, 3,4-methylenedioxybenzyl or ##STR33##and R¹³ is hydrogen or methyl; or a nontoxic pharmaceutically acceptablesalt, hydrate, solvate or N-oxide thereof.

In another preferred embodiment of the invention the compounds ofFormula I have the structure ##STR34## wherein p is 1 or 2; and R² andR³ each are independently hydrogen or (lower)alkyl, or, when R² ishydrogen, R³ also may be (lower)alkenyl, (lower)alkynyl or ##STR35## ora nontoxic pharmaceutically acceptable salt, hydrate, solvate or N-oxidethereof.

In another preferred embodiment of the invention the compounds ofFormula I have the structure ##STR36## wherein p is 1 or 2; Z is sulfuror methylene; R² and R³ each are independently hydrogen or (lower)alkyl,or, when R² is hydrogen, R³ also may be (lower)alkenyl, (lower)alkynylor ##STR37## and R⁵ and R⁶ each are independently hydrogen or(lower)alkyl, or, R⁵ and R⁶, taken together with the nitrogen atom towhich they are attached, may be piperidino; or a nontoxic,pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.

In another preferred embodiment of the invention the compounds ofFormula I have the structure ##STR38## wherein p is 1 or 2; Z is oxygenor sulfur; R² and R³ each are independently hydrogen or (lower)alkyl,or, when R² is hydrogen, R³ may also be (lower)alkenyl, (lower)alkynyl,pyridylmethyl or ##STR39## and R⁵ and R⁶ each are independently hydrogenor (lower)alkyl, or, when R⁵ is hydrogen, R⁶ also may be (lower)alkenylor (lower)alkynyl; or R⁵ and R⁶, taken together with the nitrogen towhich they are attached, may be pyrrolidino, methylpyrrolidino,morpholino, thiomorpholino, piperidino, methylpiperidino,dimethylpiperidino, homopiperidino or heptamethyleneimino; or a nontoxicpharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof.

In another preferred embodiment of the invention the compounds ofFormula I have the structure ##STR40## wherein p is 1 or 2; Z is oxygenor sulfur; R² and R³ each are independently hydrogen or (lower)alkyl,or, when R² is hydrogen, R³ may be (lower)alkenyl, (lower)alkynyl,pyridylmethyl or ##STR41## or a nontoxic pharmaceutically acceptablesalt, hydrate, solvate or N-oxide thereof.

As presently envisaged, the particularly preferred compounds of thisinvention are

(a)3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

(b)3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide,

(c)3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-ethylamino-1,2,5-thiadiazole1-1-dioxide,

(d)3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(n-propyl)amino-1,2,5-thiadiazole1,1-dioxide,

(e)3-Allylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide,

(f)3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(2-propynyl)amino-1,2,5-thiadiazole1,1-dioxide;

(g)3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole1,1-dioxide,

(h)3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole1-oxide,

(i)3-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

(j)3-{4-(5-Dimethylamino-2-furyl)butylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

(k)3-Methylamino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

(l)3-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

(m)3-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-(2-propynyl)amino-1,2,5-thiadiazole1,1-dioxide,

(n)3-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(o)3-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole1,1-dioxide,

(p)3-{2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

(q)3-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

(r)3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-ethylamino-1,2,5-thiadiazole1-oxide,

(s)3-Amino-4-{3-[3-(4-methylpiperidinomethyl)phenoxy]propylamino}-1,2,5-thiadiazole1,1-dioxide,

(t)3-Amino-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide,

(u)3-Benzylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide,

(v)3-{2-[(3-{Dimethylaminomethyl}phenyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

(w)3-Amino-4-{2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide,

(x)3-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide,

(y)3-Amino-4-{4-(5-dimethylaminomethyl-2-furyl)butylamino}-1,2,5-thiadiazole1,1-dioxide,

(z)3-Amino-4-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide,

(aa)3-Butylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide,

(bb)3-Cyclopropylmethylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide,

(cc)3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-[(2-pyridyl)methylamino]-1,2,5-thiadiazole1,1-dioxide,

(dd)3-Amino-4-{3-[3-(4-methylpiperidinomethyl)phenoxy]propylamino}-1,2,5-thiadiazole1-oxide,

(ee)4-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-3-(1-propylamino)-1,2,5-thiadiazole1,1-dioxide,

(ff)3-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide,

(gg)3-{3-[3-(hexamethyleneiminomethyl)phenoxy]propylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

(hh)3-[3-(3-dimethylaminomethylphenoxy)propylamino]-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

(ii)3-Amino-4-{3-[3-(hexamethyleneiminomethyl)phenoxy]propylamino}-1,2,5-thiadiazole1-oxide,

(jj)4-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-3-(3-pyridyl)methylamino-1,2,5-thiadiazole1,1-dioxide,

(kk)3-Amino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

(ll)3-Methylamino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

(mm)3-Amino-4-[3-(3-dimethylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(nn)3-Amino-4-{3-[3-(heptamethyleneiminomethyl)phenoxy]propylamino}-1,2,5-thiadiazole1-oxide,

(oo)3-[(3-Pyridyl)methylamino]-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(pp)3-Amino-4-{2-[(2-{2-methylguanidino}thiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide,

(qq)3-Methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

(rr)3-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

(ss)3-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-ethylamino-1,2,5-thiadiazole1,1-dioxide,

(tt)3-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

(uu) 3-Amino-4-[3-(3-guanidinophenoxy)propylamino]-1,2,5-thiadiazole1-oxide.

In another aspect, this invention relates to novel starting materialshaving the formula ##STR42## in which each R⁷ is a leaving groupselected from halogen, (lower)alkoxy, (lower)alkylthio and phenoxy orphenylthio which optionally contain 1 or 2 substituents selected fromhalogen, (lower)alkyl, (lower)alkoxy and nitro. In a preferredembodiment of the compounds of Formula IIa, each R⁷ is (lower)alkoxy,phenoxy or substituted phenoxy; most preferably, each R⁷ is methoxy.

In still another aspect, this invention relates to novel intermediatesof the formula ##STR43## wherein p is 1 or 2;

R⁷ is a leaving group selected from halogen, (lower)alkoxy,(lower)alkylthio, phenoxy, phenylthio, substituted phenoxy andsubstituted phenylthio wherein the phenyl ring may contain 1 or 2substituents selected from halogen, (lower)alkyl, (lower)alkoxy andnitro; and

R¹² is A(CH₂)_(m) Z(CH₂)_(n) NH--, R² R³ N-- or HS(CH₂)_(n) NH--; inwhich R² and R³ each are independently hydrogen, (lower)alkyl,(lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl(lower)alkyl,hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl,(lower)alkylthio(lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl orcyano(lower)alkyl, or, when R² is hydrogen, R³ may also becyclo(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)alkyl,di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl,piperidino(lower)alkyl, morpholino(lower)alkyl, piperazino(lower)alkyl,pyridyl(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridylring may contain one substituent selected from (lower)alkyl,(lower)alkoxy, hydroxy, amino and halogen, amino, (lower)alkylamino,di(lower)alkylamino, hydroxy, (lower)alkoxy, 2,3-dihydroxypropyl, cyano,amidino, (lower)alkylamidino, A'--(CH₂)_(m') Z'(CH₂)_(n') --, phenyl,phenyl(lower)alkyl, substituted phenyl or substitutedphenyl(lower)alkyl, wherein the phenyl ring may contain one or twosubstituents independently selected from (lower)alkyl, hydroxy,(lower)alkoxy and halogen or one substituent selected frommethylenedioxy, trifluoromethyl and di(lower)alkylamino; or R² and R³,taken together, may be --CH₂ CH₂ X(CH₂)_(r) --;

r is an integer of from 1 to 3, inclusive;

X is methylene, sulfur, oxygen or N-R⁴, provided that, when p is 2 andR⁷ is methoxy, R² and R³ taken together with the nitrogen to which theyare attached, may not be morpholino, and that, when r is 1, X ismethylene;

R⁴ is hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl,(lower)alkanoyl or benzoyl;

m and m' each are independently an integer of from zero to 2, inclusive;

n and n' each are independently an integer of from 2 to 4, inclusive;

Z and Z' each are independently sulfur, oxygen or methylene;

A and A' each are independently phenyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl,oxadiazolyl, furyl, thienyl or pyridyl; provided that A and A'independently may contain one or two substituents, the first substituentbeing selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen,amino, hydroxymethyl, (lower)alkoxy, ##STR44## and the secondsubstituent being selected from (lower)alkyl, hydroxy, trifluoromethyl,halogen, amino, hydroxymethyl and (lower)alkoxy;

q is an integer of from 0 to 6, inclusive;

R¹⁴ and R¹⁵ independently are hydrogen or (lower)alkyl, or if R¹⁴ ishydrogen, R¹⁵ also may be (lower)alkanoyl or benzoyl, or R¹⁴ and R¹⁵,taken together, may be ethylene; and

R⁵ and R⁶ each are independently hydrogen, (lower)alkyl, (lower)alkenyl,(lower)alkynyl, (lower)alkoxy(lower)alkyl, cyclo(lower)alkyl, phenyl orphenyl(lower)alkyl, provided that R⁵ and R⁶ may not both becyclo(lower)alkyl or phenyl; or R⁵ and R⁶, taken together with thenitrogen atom to which they are attached, may be pyrrolidino,methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino,piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino,N-methylpiperazino, homopiperidino, heptamethyleneimino oroctamethyleneimino;

or a salt, hydrate, solvate or N-oxide thereof.

In a more preferred embodiment of the compounds of Formula XVI, R¹² isA(CH₂)_(m) Z(CH₂)_(n) NH--in which A is phenyl, imidazolyl, thiazolyl,furyl, thienyl or pyridyl, each of which may contain one or twosubstituents, the first substituent being selected from (lower)alkyl,##STR45## and the second substituent being selected from (lower)alkyl; Zis sulfur, oxygen or methylene; m is zero or one; n is two or three; R¹⁴and R¹⁵ independently are hydrogen or (lower)alkyl, or R¹⁴ and R¹⁵,taken together, may be ethylene; R⁵ and R⁶ each are independentlyhydrogen or (lower)alkyl; or R⁵ and R⁶, taken together with the nitrogenatom to which they are attached, may be pyrrolidino, methylpyrrolidino,dimethylpyrrolidino, morpholino, thiomorpholino, piperidino,methylpiperidino, dimethylpiperidino, hydroxypiperidino,N-methylpiperazino, homopiperidino, heptamethyleneimino oroctamethyleneimino; and R⁷ is (lower)alkoxy.

In another more preferred embodiment of the compounds of Formula XVI,R¹² is R² R³ N-- in which R² and R³ each are independently hydrogen,(lower)alkyl, (lower)alkenyl, (lower)alkynyl orcyclo(lower)alkyl(lower)alkyl, or, when R² is hydrogen, R³ also may bepyridyl(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridylring may contain one substituent selected from (lower)alkyl,(lower)alkoxy, hydroxy, amino and halogen, A'(CH₂)_(m') Z'(CH₂)_(n') --,phenyl(lower)alkyl or 3,4-methylenedioxybenzyl; m' is zero or one, n' istwo or three, Z' is sulfur, oxygen or methylene; A' is phenyl,imidazolyl, thiazolyl, furyl, thienyl or pyridyl, each of which maycontain one or two substituents, the first substituent being selectedfrom (lower)alkyl, ##STR46## and the second substituent being selectedfrom (lower)alkyl; R¹⁴ and R¹⁵ independently are hydrogen or(lower)alkyl, or R¹⁴ and R¹⁵, taken together, may be ethylene; R⁵ and R⁶each are independently hydrogen or (lower)alkyl; or R⁵ and R⁶, takentogether with the nitrogen atom to which they are attached, may bepyrrolidino, methylpyrrolidino, dimethylpyrrolidino, morpholino,thiomorpholino, piperidino, methylpiperidino, dimethylpiperidino,hydroxypiperidino, N-methylpiperazino, homopiperidino,heptamethyleneimino or octamethyleneimino; and R⁷ is (lower)alkoxy. In aparticularly preferred embodiment, the compound is3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide.

In another more preferred embodiment of the compounds of Formula XVI,R¹² is HS(CH₂)_(n) NH--; in which n is an integer of from two to fourand R⁷ is (lower)alkoxy.

In a particularly preferred embodiment of the compounds of Formula XVI,R¹² is ##STR47## in which Z is sulfur or methylene, R¹⁶ is methyl andR¹³ is hydrogen or methyl, or R¹⁶ and R¹³, taken together with thenitrogen atom to which they are attached, may be piperidino; and R⁷ is(lower)alkoxy.

In another particularly preferred embodiment of the compounds of FormulaXVI, R¹² is ##STR48## in which Z is sulfur or methylene; R¹⁴ and R¹⁵independently are hydrogen or methyl, or R¹⁴ and R¹⁵, taken together,may be ethylene; and R⁷ is (lower)alkoxy.

In another particularly preferred embodiment of the compounds of FormulaXVI, R¹² is ##STR49## in which R¹³ is hydrogen or methyl; Z is sulfur ormethylene; and R⁷ is (lower)alkoxy.

In another particularly preferred embodiment of the compounds of FormulaXVI, R¹² is ##STR50## in which R¹³ is hydrogen or methyl; Z is sulfur ormethylene; and R⁷ is (lower)alkoxy.

In another particularly preferred embodiment of the compounds of FormulaXVI, R¹² is ##STR51## in which R⁵ and R⁶ each are independently hydrogenor (lower)alkyl, or, R⁵ and R⁶, taken together with the nitrogen atom towhich they are attached, may be piperidino; Z is sulfur or methylene;and R⁷ is (lower)alkoxy.

In another particularly preferred embodiment of the compounds of FormulaXVI, R¹² is ##STR52## in which Z is oxygen or sulfur; R⁵ and R⁶ each areindependently hydrogen or (lower)alkyl, or, when R⁵ is hydrogen, R⁶ alsomay be (lower)alkenyl or (lower)alkynyl; or R⁵ and R⁶, taken togetherwith the nitrogen to which they are attached, may be pyrrolidino,methylpyrrolidino, morpholino, thiomorpholino, piperidino,methylpiperidino, dimethylpiperidino, homopiperidino orheptamethyleneimino; and R⁷ is (lower)alkoxy.

In another particularly preferred embodiment of the compounds of FormulaXVI, R¹² is ##STR53## in which Z is oxygen or sulfur; and R⁷ is(lower)alkoxy.

In still another aspect, this invention relates to novel intermediatesof the formula ##STR54## wherein p is 1 or 2;

n is an integer of from 2 to 4, inclusive;

R² and R³ each are independently hydrogen, (lower)alkyl, (lower)alkenyl,(lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower)alkyl,(lower)alkoxy(lower)alkyl, (lower)alkylthio(lower)alkyl, 2-fluoroethyl,2,2,2-trifluoroethyl or cyano(lower)alkyl, or, when R² is hydrogen, R³may also be cyclo(lower)alkyl, amino(lower)alkyl,(lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl,pyrrolidino(lower)alkyl, piperidino(lower)alkyl, morpholino(lower)alkyl,piperazino(lower)alkyl, pyridyl(lower)alkyl, substitutedpyridyl(lower)alkyl wherein the pyridyl ring may contain one substituentselected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen,amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)alkoxy,2,3-dihydroxypropyl, cyano, amidino, (lower)alkylamidino, A'--(CH₂)_(m')Z'(CH₂)_(n') --, phenyl, phenyl(lower)alkyl, substituted phenyl orsubstituted phenyl(lower)alkyl, wherein the phenyl ring may contain oneor two substituents independently selected from (lower)alkyl, hydroxy,(lower)alkoxy and halogen or one substituent selected frommethylenedioxy, trifluoromethyl and di(lower)alkylamino; or R² and R³,taken together, may be --CH₂ CH₂ X(CH₂)_(r) --;

r is an integer of from 1 to 3, inclusive;

X is methylene, sulfur, oxygen or N-R⁴, provided that, when r is 1, X ismethylene;

R⁴ is hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl,(lower)alkanoyl or benzoyl;

m' is an integer of from zero to 2, inclusive;

n' is an integer of from 2 to 4, inclusive;

Z' is sulfur, oxygen or methylene;

A' is phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl,triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl;provided that A' may contain one or two substituents, the firstsubstituent being selected from (lower)alkyl, hydroxy, trifluoromethyl,halogen, amino, hydroxymethyl, (lower)alkoxy, ##STR55## and the secondsubstituent being selected from (lower)alkyl, hydroxy, trifluoromethyl,halogen, amino, hydroxymethyl and (lower)alkoxy;

q is an integer of from 0 to 6, inclusive;

R¹⁴ and R¹⁵ independently are hydrogen or (lower)alkyl, or, if R¹⁴ ishydrogen, R¹⁵ also may be (lower)alkanoyl or benzoyl, or R¹⁴ and R¹⁵,taken together, may be ethylene; and

R⁵ and R⁶ each are independently hydrogen, (lower)alkyl, (lower)alkenyl,(lower)alkynyl, (lower)alkoxy(Lower)alkyl, cyclo(lower)alkyl, phenyl orphenyl(lower)alkyl, provided that R⁵ and R⁶ may not both becyclo(lower)alkyl or phenyl; or R⁵ and R⁶, taken together with thenitrogen atom to which they are attached, may be pyrrolidino,methylpyrrolidino, dimethylpyrrolidino, morpholino, thiomorpholino,piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino,N-methylpiperazino, homopiperidino, heptamethyleneimino oroctamethyleneimino; or a salt, hydrate, solvate or N-oxide thereof.

In a more preferred embodiment of the compounds of Formula XVII, R² andR³ each are independently hydrogen, (lower)alkyl, (lower(alkenyl,(lower)alkynyl or cyclo(lower)alkyl(lower)alkyl, or, when R² ishydrogen, R³ also may be pyridyl(lower)alkyl, substitutedpyridyl(lower)alkyl wherein the pyridyl ring may contain one substituentselected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen,A'--(CH₂)_(m') Z'(CH₂)_(n') --, phenyl(lower)alkyl or3,4-methylenedioxybenzyl; m' is an integer of from zero to twoinclusive; n and n' each are independently an integer of from 2 to 4,inclusive; Z' is sulfur, oxygen or methylene; A' is phenyl, imidazolyl,thiazolyl, furyl, thienyl or pyridyl, each of which may contain one ortwo substituents, the first substituent being selected from(lower)alkyl, ##STR56## and the second substituent being selected from(lower)alkyl; and R⁵ and R⁶ each are independently hydrogen or(lower)alkyl.

In another more preferred embodiment of the compounds of Formula XVII, nis 2; R² and R³ each are independently selected from hydrogen,(lower)alkyl, (lower)alkenyl, (lower)alkynyl and phenyl(lower)alkyl, or,when R² is hydrogen, R³ may be ##STR57## in which Z is sulfur ormethylene and R¹³ is hydrogen or methyl.

In another more preferred embodiment of the compounds of Formula XVII, nis 2; R² is hydrogen; and R³ is ##STR58## in which Z is oxygen orsulfur; R⁵ and R⁶ each are independently hydrogen or (lower)alkyl, or,when R⁵ is hydrogen, R⁶ also may be (lower)alkenyl or (lower)alkynyl; orR⁵ and R⁶, taken together with the nitrogen to which they are attached,may be pyrrolidino, morpholino, piperidino or homopiperidino.

In another more preferred embodiment of the compounds of Formula XVII, nis 2; R² is hydrogen and R³ is ##STR59## in which Z is oxygen or sulfur.

As used herein, the term nontoxic pharmaceutically acceptable salt meansthe salt of a compound of Formula I with a nontoxic pharmaceuticallyacceptable organic or inorganic acid. Such acids are well known andinclude hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric, maleic, fumaric, succinic, oxalic, benzoic, methanesulfonic,ethanedisulfonic, benzenesulfonic, acetic, propionic, tartaric, citric,camphorsulfonic, and the like. The salts are made by methods known inthe art. It will be appreciated by those skilled in the art that some ofthe compounds of Formula I and intermediates disclosed herein will formdi-salts, tri-salts, etc. It is also to be understood that salts of theintermediates are not limited to salts with nontoxic pharmaceuticallyacceptable acids when such intermediates are not themselves used asmedicaments.

We have found that many of the compounds of Formula I produced hereintenaciously hold solvents from which they are crystallized. In somecases it appears that the products are true solvates, while in othercases the products may merely retain adventitious solvent or be amixture of solvate plus some adventitious solvent. Although the solventcan be removed by drying at elevated temperature, this often changed anicely crystalline product into a gummy solid. Because the solvatedproducts usually had quite sharp melting points, our usual practice wasto dry the products at room temperature. Where solvent was retained evenafter lengthy drying, the amount of solvent was determined, such as byNMR. The Examples below give the amount of solvent (where appropriate)and the analyses and melting points are those of the solvated productunless otherwise specified.

For therapeutic use, the pharmacologically active compounds of thisinvention will normally be administered as a pharmaceutical compositioncomprising as the (or an) essential active ingredient at least one suchcompound in the basic form or in the form of a nontoxic pharmaceuticallyacceptable acid addition salt, in association with a pharmaceuticallyacceptable carrier.

The pharmaceutical compositions may be administered orally, parenterallyor by rectal suppository. A wide variety of pharmaceutical forms may beemployed. Thus, if a solid carrier is used, the preparation may betableted, placed in a hard gelatin capsule in powder or pellet form, orin the form of a troche or lozenge. If a liquid carrier is employed, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile solution for injection, or an aqueous or non-aqueousliquid suspension. The pharmaceutical compositions are prepared byconventional techniques appropriate to the desired preparation.

The dosage of the compounds of this invention will depend not only onsuch factors as the weight of the patient, but also on the degree ofgastric acid inhibition desired and the potency of the particularcompound being utilized. The decision as to the particular dosage to beemployed is within the discretion of the physician. In the Two HourPylorus Ligated Rat test described below, cimetidine has an ED₅₀ ofapproximately 9 μmoles/kg. The usual human adult dosage of cimetidine is300 mg, given four times a day. The usual human adult starting dosagesof the compounds of this invention are readily determined from theirED₅₀ in this same test. Thus, if the ED₅₀ is 0.9 μmoles, the usualstarting dosage would be approximately 30 mg, given four times a day.With an ED₅₀ of 0.09 μmoles/kg, the usual starting dosage would beapproximately 3 mg, given four times a day, etc. These starting dosages(and the number of times administered per day) may, of course, be variedby titration of the dosage to the particular circumstances of thespecific patient. With the preferred compounds of this invention, eachdosage unit will contain the active ingredient in an amount of fromabout 0.5 mg to about 150 mg, and most preferably from about 2 mg toabout 50 mg. The active ingredient will preferably be administered inequal doses from two to four times a day. The daily dosage regimen willpreferably be from 1 mg to about 600 mg, and most preferably from about4 mg to about 200 mg.

Histamine H₂ -receptor antagonists have been shown to be effectiveinhibitors of gastric secretion in animals and man, Brimblecombe et al.,J. Int. Med. Res., 3, 86 (1975). Clinical evaluation of the histamine H₂-receptor antagonist cimetidine has shown it to be an effectivetherapeutic agent in the treatment of peptic ulcer disease, Gray et al.,Lancet, 1, 8001 (1977). One of the standard animal models fordetermining gastric antisecretory activity of histamine H₂ -antagonistsis the pylorus ligated rat. Table 1, below, gives the gastricantisecretory ED₅₀ (in μmoles/kg.) in the pylorus ligated rat for manyof the compounds of this invention.

Determination of Gastric Antisecretory Activity in the Two Hour PylorusLigated (Shay) Rat

The pyloric ligation procedure in the rat was designed by Shay et al.,Gastroenterology, 5, 53 (1945) for the study of perforating gastriculcers; however, as the method became known, it was also employed as ameans of studying rat gastric secretion, Shay et al., Gastroenterology,26, 906 (1954), Brodie, D, A. Am. J. Dig. Dis., 11, 231 (1966). Amodification of this procedure is presently used to evaluate compoundsfor gastric antisecretory activity.

Male Long Evans rats, 280-300 gm., are used. The animals are placed inindividual cages and fasted for 24 hours with free access to water.Under ether anesthesia, the stomach is reached through a midlineincision, and a cotton-thread ligature is placed around the pylorus.After wound closure, ether administration is stopped and the testcompound or control vehicle is administered either intraperitoneally orsubcutaneously in a volume of 1 ml./kg. All compounds are solubilizedwith one equivalent of HCl and brought to the proper volume with water.The animals are returned to their cages from which the water bottleshave been removed and two hours later are sacrificed with ether. Thestomach is removed and the two hour gastric collection is drained into agraduated test tube for volume determination. Titratable acidity ismeasured by titrating a one ml. sample to pH 7.0 with 0.02 NaOH, usingan Autoburet and electrometric pH meter (Radiometer). Titratable acidoutput is calculated in microequivalents by multiplying the volume inmilliliters by the acid concentration in milliequivalents per liter. Thepercent inhibition of acid output is calculated as follows ##EQU1## Atleast five rats are used at each dosage level, and a minimum of threedosage levels are utilized for determination of a dose response curve.Initially this test was conducted utilizing intraperitoneal injection ofthe test compound or control vehicle. However, it was subsequently foundthat the test was somewhat more sensitive when subcutaneous injectionswere utilized, and all subsequent tests were conducted via thesubcutaneous route. The route of administration of each compound isnoted in Table 1.

                  TABLE 1                                                         ______________________________________                                        Effect of Compounds of this Invention on Gastric Acid                         Output in the Two Hour Pylorus Ligated Rat                                    Compound of                                                                              Route or    ED.sub.50 *                                            Example No.                                                                              Administration                                                                            μmoles/kg.                                          ______________________________________                                        1          i.p.        12.5      (4.90-33.0)                                  2          s.c.        ˜100                                             3          i.p.        0.46      (0.26-0.74)                                  7          i.p.        31.1      (11.1-82.8)                                  11 B       i.p.        0.69      (0.31-1.33)                                  11 C       s.c.        0.20      (0.03-2.9)                                   12         i.p.        0.28      (0.11-0.69)                                  13         s.c.        0.46      (0.02-3.1)                                   14         s.c.        ˜25                                              17         s.c.        33        (8.7-141)                                    18         s.c.        0.38      (0.02-5.33)                                  19         s.c.        0.34      (0.15-0.81)                                  20 A       s.c.        1.15      (0.32-3.7)                                   21         s.c.        0.30      (0.09-1.0)                                   28         s.c.        1.39      (0.39-4.91)                                  31         i.p.        0.41      (0.19-0.81)                                  32         i.p.        0.08      (0.03-0.15)                                  33         s.c.        0.57      (0.16-1.84)                                  35         s.c.        0.08      (0.02-0.22)                                  36         s.c.        1.59      (0.48-6.46)                                  51         s.c.        55        (8.8-930)                                    52         s.c.        ˜350                                             65         s.c.        0.07      (0.02-0.32)                                  84         s.c.        0.15      (0.02-0.53)                                  85         s.c.        0.14      (0.05-0.41)                                  86         s.c.        0.04      (0.015-0.12)                                 87         s.c.        0.02      (0.006-0.04)                                 88         s.c.        0.08      (0.04-0.22)                                  89         s.c.        0.25      (0.07-0.84)                                  90         s.c.        0.86      (0.24-2.69)                                  91         s.c.        1.3       (0.36-3.9)                                   92         s.c.        0.24      (0.09-0.71)                                  93         s.c.        0.14      (0.07-0.32)                                  94         s.c.        0.44      (0.08-1.9)                                   95         s.c.        ˜15                                              96         s.c.        ˜15                                              97         s.c.        ˜3                                               98         s.c.        0.52      (0.08-2.33)                                  99         s.c.        32        5.7-200)                                     100        s.c.        1.6       (0.38-5.5)                                   101        s.c.        68        (10-750)                                     102        s.c.        ˜15                                              103        s.c.        0.54      (0.21-1.4)                                   104        s.c.        0.61      (0.15-1.88)                                  105        s.c.        1.65      (0.45-4.45)                                  106        s.c.        ˜80                                              107        s.c.        23        (5.1-110)                                    108        s.c.        2.2       (0.54-8.9)                                   109        s.c.        1.4       (0.51-3.9)                                   110        s.c.        0.05      (0.03-0.14)                                  111        s.c.        0.64      (0.17-2.5)                                   112        s.c.        1.2       (0.47-2.9)                                   113        s.c.        0.07      (0.03-0.14)                                  114        s.c.        ˜15                                              115        s.c.        0.57      (0.20-1.6)                                   116        s.c.        >10                                                    117        s.c.        ˜0.5                                             118        s.c.        0.066     (0.018-0.19)                                 119        s.c.        >10                                                    120        s.c.        ˜5                                               121        s.c.        0.19      (0.055-0.56)                                 122        s.c.        ˜10.0                                            123        s.c.        >10                                                    124        s.c.        >10                                                    125        s.c.        ˜10                                              127        s.c.        >10                                                    128        s.c.        ˜10                                              129        s.c.        ˜1                                               130        s.c.        2.3       (0.79-14)                                    131        s.c.        ˜0.5                                             132        s.c.        0.025     (0.007-0.069)                                133        s.c.        0.061     (0.019-0.24)                                 134        s.c.        0.024     (0.011-0.050)                                135        s.c.        0.57      (0.29-1.12)                                  144 a      s.c.        0.095     (0.033-0.30)                                 144 b      s.c.        0.025     (0.0087-0.065)                               144 c      s.c.        0.14      (0.034-0.44)                                 144 d      s.c.        0.91      (0.36-3.2)                                   145 a      s.c.        0.056     (0.021-0.18)                                 145 b      s.c.        ˜0.06                                            145 c      s.c.        0.025     (0.0098-0.057)                               145 d      s.c.        0.05      (0.005-0.2)                                  146 a      s.c.        0.023     (0.0091-0.046)                               146 d      s.c.        0.28      (0.66-1.21)                                  149        s.c.        ˜0.08                                            151        s.c.        0.9       (0.15-3.5)                                   ______________________________________                                         *Numbers in parentheses are the 95% confidence limits                    

Some of the compounds of this invention were also tested, and showedactivity, in the Isolated Guinea Pig Right Atria Test, in the GastricFistula Dog Test (intravenous) and the Heidenhain Pouch Dog Test (oral).The first two tests were conducted according to the procedures describedin our colleagues U.S. Pat. No. 4,112,234. The Heidenhain Pouch Dog Testfollowed the general procedure of Grossman and Konturek,Gastroenterology, 66, 517 (1974).

Celite is a registered trademark of the Johns-Manville ProductsCorporation for diatomaceous earth. Skellysolve B is a registeredtrademark of the Skelly Oil Company for a petroleum ether fractionboiling at 60°-68°, consisting essentially of n-hexane.

The term "flash chromatography" used in some of the Examples refers to arelatively new chromatographic technique described by W. C. Still et al.in J. Org. Chem., 43, 2923-2925 (1978). It utilizes more finely dividedchromatographic media and pressures somewhat above atmospheric pressure,to give faster chromatographic separations.

In the following examples, all temperatures are given in degreesCentigrade.

EXAMPLE 13-{2-[(5-Methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-(2-propynyl)amino-1,2,5-thiadiazole1,1-dioxide

A.3-{2-[(5-Methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide

To a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (2.0 g; 11.2 mmoles) [prepared according to the proceduredescribed in J. Org. Chem., 40, 2743 (1975)] in 200 ml of methanol atambient temperature was added a solution of2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine (from thedihydrochloride, 2.73 g; 11.2 mmoles) [prepared according to BelgianPatent 779,775] in 25 ml of methanol. After stirring for 30 minutes, amethanolic solution of the title compound was produced. The TLC[Silica/CH₂ Cl₂ :CH₃ OH (90:10)] gave Rf=0.44.

B.3-{2-[(5-Methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-(2-propynyl)amino-1,2,5-thiadiazole1,1-dioxide

To the methanolic solution of the product of Step A was added 7 ml of2-propynylamine. After stirring at ambient temperature for 20 minutes,the reaction mixture was evaporated under reduced pressure, and theresidual oil was placed on silica gel and chromatographed by gradientelution using methylene chloride-methanol. The appropriate fractionswere combined to yield 2.74 g of the title compound as an oil.

An additional purification was achieved by combining the above materialwith that obtained in an identical second experiment and the mixtureplaced on silica gel and chromatographed by gradient elution usingmethylene chloride-methanol. The appropriate fractions were combinedwith methanol and evaporated under reduced pressure to yield the titlecompound (2.93 g) as a friable solid, mp 82°-103°; the NMR spectrum (100MHz) in d₆ dimethyl sulfoxide showed the presence of 1/3 mole ofmethanol.

Anal. Calcd for C₁₂ H₁₆ N₆ O₂ S₂.1/3CH₃ OH: C, 42.19; H, 4.97; N, 23.95;S, 18.27. Found: C, 42.05; H, 5.05; N, 24.01; S, 18.45.

EXAMPLE3-{2-[(5-Methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

To a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (2.5 g; 14.0 mmoles) in 250 ml of dry methanol that had beencooled to 2° in an ice-water bath was added dropwise over a period of 25minutes a solution of2-[(5-methyl-1-H-imidazol-4-yl)methylthio]ethylamine (from thedihydrochloride, 3.42 g; 14.0 mmoles) in 25 ml of methanol. Afterstirring at 2° for 20 minutes, anhydrous methylamine was bubbled intothe solution for 6 minutes and stirring was continued at ambienttemperature for 30 minutes. The reaction mixture was evaporated underreduced pressure and the residue was placed on 50 g of silica gel andchromatographed by gradient elution using methylene chloride-methanol.The appropriate fractions were combined to give 3.2 g of the titlecompound. Additional purification of the product using columnchromatography gave an analytical sample of the title compound as anamorphous solid, mp 98°-110°. The NMR spectrum (100 MHz) in d₆ dimethylsulfoxide gave the following resonances δ: 7.46 (s, 1H); 3.70 (s, 2H);2.53 (t, 2H); 2.86 (s, 3H); 2.72 (t, 2H); 2.15 (s, 3H).

Anal. Calcd. for C₁₀ H₁₆ N₆ O₂ S₂ : C, 37.96; H, 5.09; N, 26.56; S,20.27. Found (corr. for 1.60% H₂ O): C, 37.79; H, 5.16; N, 26.52; S,20.24.

EXAMPLE 33-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

To a well stirred solution at -10° of3-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide [prepared from the dihydrochloride of2-{(5-methyl-1H-imidazol-4-yl)methylthio}ethylamine (2.73 g; 11.2 mmole)by the procedure of Step A of Example 1] was rapidly added a solution of2-[(2-quanidinothiazol-4-yl)methylthio]ethylamine (from thedihydrochloride, 3.41 g; 11.2 mmoles) [prepared according to theprocedure described in South African Patent 78/2129] in 35 ml ofmethanol. After stirring at -10° for 30 minutes, the solution wasallowed to warm to ambient temperature. The reaction mixture wasevaporated under reduced pressure and the residue was placed on 45 g ofsilica gel and chromatographed using 1 liter of methylenechloride-methanol (4:1). The appropriate fractions were combined andevaporated, and the residue (5.82 g) was placed on 80 g of aluminumoxide and chromatographed using a gradient elution of ethylacetate-methanol. The appropriate fractions were combined, filteredthrough Celite and evaporated under high vacuum to yield the titlecompound (2.5 g) as an amorphous solid containing approximately 2/3 moleof ethyl acetate, as ascertained by the NMR spectrum (100 MHz) in d₆dimethyl sulfoxide.

Anal. Calcd for C₁₆ H₂₄ N₁₀ O₂ S₄.2/3C₄ H₈ O₂ : C, 38.96; H, 5.14; N,24.34; S, 22.29. Found: C, 39.08; H, 4.96; N, 24.48; S, 22.26.

EXAMPLE 43-{2-[(5-Methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

A. 3,4-Dimethoxy-1,2,5-thiadiazole 1-oxide

A solution of 3,4-dimethoxy-1,2,5-thiadiazole (35.2 g; 24.1 mmoles)[prepared according to the procedure described in J. Org. Chem., 40,2749 (1975)] in 100 ml of chloroform was added over a period of 3minutes to a stirred solution of m-chloroperbenzoic acid (50.7 g; 25.0mmoles; 85% assay) in 900 ml of chloroform at 20°, using a cooling bathto keep the exothermic reaction from rising above 32°. After stirringfor 3 hours at ambient temperature, the excess peracid was reacted withan additional 2.0 g of 3,4-dimethoxy-1,2,5-thiadiazole and stirred for 1hours.

The organic solution was extracted with two-300 ml portions of a 1%solution of NaHCO₃, washed with 250 ml of water, dried and evaporatedunder reduced pressure to give 47.0 g of product. Recrystallization fromisopropyl alcohol gave the title compound (34.0 g). An additionalrecrystallization from isopropyl alcohol gave an analytical sample, mp135°-137°.

Anal. Calcd for C₄ H₆ N₂ O₃ S: C, 29.63; H, 3.72; N, 17.27; S, 19.77.Found: C, 29.53; H, 3.75; N, 17.26; S, 19.83.

B.3-{2-[(5-Methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

A solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide obtained from theabove Step A is reacted with an equimolar amount of2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamine and the resulting3-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1-oxide is treated with an excess of methylamine, and the title compoundis thereby produced.

EXAMPLE 53-{2-[(5-Hydroxymethyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

2-[(5-Hydroxymethyl-1H-imidazol-4-yl)methylthio]ethylamine [preparedaccording to the procedure described in Belgian Pat. No. 843,840] isreacted with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide and theresultant3-{2-[(5-hydroxymethyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide is treated with excess methylamine according to the generalprocedure described in Example 2, and the title compound is therebyproduced.

EXAMPLE 6

The general procedure of Example 5 is repeated except that the2-[(5-hydroxymethyl-1H-imidazol-4-yl)methylthio]ethylamine utilizedtherein is replaced by an equimolar amount of

2-[(5-bromo-1H-imidazol-4-yl)methylthio]ethylamine,

2-[imidazol-4-ylmethylthio]ethylamine,

2-[imidazol-2-ylmethylthio]ethylamine,

2-[(1-methyl-imidazol-2-yl)methylthio]ethylamine,

2-[(2-methyl-1H-imidazol-4-yl)methylthio]ethylamine,

2-[(1-methyl-imidazol-4-yl)methylthio]ethylamine,

2-[(1,5-dimethyl-imidazol-4-yl)methylthio]ethylamine,

2-[(5-chloro-1-methyl-imidazol-4-yl)methylthio]ethylamine,

2-[(5-trifluoromethyl-1H-imidazol-4-yl)methylthio]ethylamine,

2-[(5-ethyl-1H-imidazol-4-yl)methylthio]ethylamine and

2-[(2-amino-1H-imidazol-4-yl)methylthio]ethylamine, respectively, [eachprepared by the general procedures described in Belgian Pat. No.779,775] and there is thereby produced

3-{2-[(5-bromo-1H-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[imidazol-4-ylmethylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[imidazol-2-ylmethylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(1-methyl-imidazol-2-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(2-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(1-methyl-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(1,5-dimethyl-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-chloro-1-methyl-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-trifluoromethyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-ethyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide and

3-{2-[(2-amino-1H-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide, respectively.

EXAMPLE 73-Hydroxy-4-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of3-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide [prepared by the procedure of Step A of Example 1] istreated with a solution of sodium hydroxide in methanol by the generalprocedure of Example 17, Step B, the title compound is produced, mp263°-265° (dec).

Anal. Calcd C₉ H₁₃ N₅ S₂ O₃ : C, 35.64; H, 4.32; N, 23.09; S, 21.13.Found: C, 35.56; H, 4.38; N, 23.01; S, 21.13.

EXAMPLE 83-{4-[(2-Guanidino-1H-imidazol-4-yl]butylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxideis successively reacted with an equimolar amount of4-[2-guanidino-1H-imidazol-4-yl]butylamine [prepared according toBelgian Pat. No. 866,156] and excess methylamine according to thegeneral procedure of Example 2, and the title compound is therebyproduced.

EXAMPLE 93-{2-[(5-Methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-(2-propynyl)amino-1,2,5-thiadiazole1,1-dioxide

Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide wth one equivalent of 2-propynylamine and treating theresultant 3-methoxy-4-propynylamino-1,2,5-thiadiazole 1,1-dioxide withone equivalent of 2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethylamineyields the title compound; identical to the product of Example 1.

EXAMPLE 103-{2-[(5-Methyl-1H-imidazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a solution of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole1,1-dioxide (prepared in Example 25, Step A) is reacted with4-chloromethyl-5-methylimidazole hydrochloride and a strong base, thetitle compound is thereby produced; identical to the product of Example2.

EXAMPLE 113-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide and3,4-bis-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

A.3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(2.41 g; 11.2 mmoles) [prepared according to the procedure described inBelgian Pat. No. 857,388] in 20 ml of dry methanol was added all at onceto a well stirred, cold (8°) suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200ml of methanol. After stirring at 8°-10° for 15 minutes, a methanolicsolution of the title compound is produced.

B.3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

Anhydrous methylamine was bubbled into the cooled (1°) methanolicsolution of the product of Step A for 6 minutes. Stirring was continuedfor 10 minutes and the mixture was evaporated under reduced pressure.The residue was placed on 45 g of silica gel and chromatographed using agradient elution of methylene chloride-methanol. The appropriatefractions, using methylene chloride-methanol (95:5) were combined inmethanol, filtered through Celite, and then concentrated under reducedpressure to give product. Recrystallization from methanol yielded thetitle compound (1.76 g), mp 82°-90°; the NMR spectrum (100 MHz) in d₆dimethyl sulfoxide showed the presence of 2/3 mole of methanol.

Anal. Calcd for C₁₃ H₂₁ N₅ O₃ S₂.2/3CH₃ OH: C, 43.10; H, 6.26; N, 18.38;S, 16.83. Found (corr. for 1.72% H₂ O): C, 43.30; H, 6.12; N, 18.57; S,16.96.

C.3,4-Bis-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

The slower eluting component using methylene chloride-methanol (9:1)from the chromatography in Step B was placed on 45 g of aluminum oxideand chromatographed using a gradient elution of ethyl acetate-methanol.The appropriate fraction was evaporated and the residue triturated underether-acetonitrile to give a colorless solid which was collected byfiltration to yield the title compound (428 mg) as a monohydrate, mp92.5°-96°.

Anal. Calcd for C₂₂ H₃₄ N₆ S₃ O₄.H₂ O: C, 47.12; H, 6.47; N, 14.99; S,17.15. Found: C, 47.28; H, 6.48; N, 15.09; S, 17.39. Calcd for H₂O=3.21%; Found H₂ O=3.32%.

EXAMPLE 123-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-ethylamino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(2.41 g; 11.2 mmoles) in 20 ml of dry methanol was added all at once toa well stirred cold (1°) suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (2.0 g; 11.2 mmoles) in 200 ml of methanol. After stirringfor 15 minutes at 1°-5°, ethylamine (4.0 ml) was added and stirring wascontinued at approximately 5° for 20 minutes. The reaction mixture wasevaporated under reduced pressure and the residue was placed on 46 g ofsilica gel and chromatographed using a gradient elution of methylenechloride-methanol. The appropriate fractions were combined, evaporatedand the gelatinous residue triturated under ether and filtered to givethe product as a colorless solid (2.81 g). Two recrystallizations frommethanol and drying over P₂ O₅ at ambient temperature for 17 hoursyielded the title compound, mp 155°-160° with variable sintering at94°-96° ; the NMR spectrum (100 MHz) in d₆ dimethyl sulfoxide showed thepresence of approximately 0.8 moles of methanol.

Anal. Calcd for C₁₄ H₂₃ N₅ O₃ S₂.0.8CH₃ OH: C, 44.54; H, 6.62; N, 17.55;S, 16.07. Found: C, 44.35; H, 6.58; N, 17.44; S, 16.18.

EXAMPLE 133-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(2-propynyl)amino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(2.41 g; 11.2 mmoles) in 20 ml of dry methanol was added dropwise over aperiod of 25 minutes to a well stirred cold (1°) suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200ml of methanol. After stirring at 1°-2° for 15 minutes, a solution of2-propynylamine (4.0 ml) in 10 ml of dry methanol was added all at once,and stirring was then continued at ambient temperature for 1 hour. Thereaction mixture was evaporated under reduced pressure and the residuewas placed on 50 g of silica gel and chromatographed using a gradientelution of methylene chloride-methanol. The appropriate fractions werecombined, evaporated and crystallized from methanol to give 4.0 g ofproduct. Recrystallization from methanol and then from isopropyl alcoholyielded the title compound (2.90 g), mp 92°-100°; the NMR spectrum (100MHz) in d₆ dimethyl sulfoxide showed the product to be solvated with 1mole of methanol.

Anal. Calcd for C₁₅ H₂₁ N₅ O₃ S₂.CH₃ OH: C, 46.25; H, 6.06; N, 16.85; S,15.43. Found: C, 46.36; H, 6.22; N, l6.95; S, 15.73.

EXAMPLE 143-Methylamino-4-{2-[(5-{[N-methyl-N-(2-propynyl)amino]methyl}-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

A. 5-{[N-methyl-N-(2-propynyl)amino]methyl}-2-furanmethanol

To furfuryl alcohol (2.49 g; 25.4 mmoles) which was cooled in anice-water bath to 5° was added N-methylpropargylamine hydrochloride (4.0g; 37.9 mmoles) and 40% formalin (3.13 ml; 41.7 mmoles), and the mixturestirred while allowed to reach ambient temperature. After 1 hour ofstirring the solution was allowed to stand at ambient temperature for41/2 days. The reaction mixture was poured into ice water, made stronglybasic with 40% aqueous NaOH and extracted with five portions ofmethylene chloride. The combined organic phase was dried, filtered andevaporated under reduced pressure to give the product as an oil(quantitative yield). Vacuum distillation yielded the title compound, bp102°-106°/0.3 mm Hg.

Anal. Calcd for C₁₀ H₁₃ NO₂ : C, 67.02; H, 7.31; N, 7.82. Found: C,66.80; H, 7.44; N, 7.93.

B.2-[(5-{[N-Methyl-N-(2-propynyl)amino]methyl}-2-furyl)methylthio]ethylamine

A solution of 5-{[N-methyl-N-(2-propynyl)amino]methyl}-2-furanmethanol(40.0 g; 223 mmoles) [prepared in Step A] in 100 ml of ice-coldconcentrated HCl was added to a cold (5°) stirred solution of cysteaminehydrochloride (27.9 g; 24.6 mmoles) in 125 ml of concentratedhydrochloric acid. The solution was allowed to stand at 0° for 21/2days, and then at ambient temperature for 7 hours to complete thereaction. The reaction mixture was cooled in an ice-water bath, dilutedwith 200 ml of water, made strongly alkaline with 40% aqueous NaOH, andthen extracted with three portions of methylene chloride. The combinedorganic phase was dried, filtered, and evaporated under reduced pressureto give the product as a thick oil (46.4 g). A rapid vacuum distillationof the oil yielded the title compound, bp 136°-140°/0.2 mm Hg.

Anal. Calcd for C₁₂ H₁₈ N₂ OS: C, 60.47; H, 7.61; N, 11.76; S, 13.46.Found: C, 59.82; H, 7.68; N, 11.61; S, 13.27.

C.3-Methylamino-4-{2-[(5-{[N-methyl-N-(2-propynyl)amino]methyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

To a stirred cold (3°) suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (2.0 g; 11.2 mmoles) in 200 ml of dry methanol was added asolution of2-[(5-{[N-methyl-N-(2-propynyl)amino]methyl}-2-furyl)methylthio]ethylamine(2.68 g; 11.2 mmoles) [prepared in Step B]. After stirring at 3°-7° for15 minutes, methylamine was bubbled into the solution for 16 minutes.The reaction mixture was evaporated under reduced pressure and the oilyresidue was placed on 100 g of silica gel and chromatographed using agradient of acetonitrile-methanol. The appropriate fractions werecombined and rechromatographed on 100 g of silica gel using a gradientof methylene chloride-methanol. The appropriate fractions was dissolvedin methylene chloride and extracted with 1% aqueous NaOH. The aqueousphase was brought to pH 9 with 5% aqueous HCl and the separated oil wasextracted with three portions of methylene chloride. The combinedextracts were dried, filtered and evaporated under reduced pressure togive product as a foam. Recrystallization from isopropyl alcohol yieldedthe title compound, mp. 50°-51°, clear melt 54°-56°; the NMR spectrum(100 MHz) in D₆ dimethyl sulfoxide showed the presence of approximately1/4 mole of isopropyl alcohol.

Anal. Calcd for C₁₅ H₂₁ N₅ O₃ S₂.1/4C₃ H₈ O: C, 47.47; H, 5.82; N,17.57; S, 16.09. Found: C, 47.51; H, 6.21; N, 16.40; S, 15.97.

EXAMPLE 153-{2-[(5-Dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A. 5-Dimethylaminomethyl-3-methyl-2-furanmethanol

A mixture containing 3-methyl-2-furfuryl alcohol (11.2 g; 0.1 mole[prepared according to the procedure described in J. Am. Chem. Soc., 72,2195 (1950)], dimethylamine hydrochloride (12.23 g; 0.15 mole) and 37%aqueous formaldehyde (12 ml, 0.15 mole) was stirred for 2.5 hours atapproximately 5°, and then at ambient temperature overnight. Thesolution was heated for 10 minutes on a steam bath, diluted with 12 mlof water and basified with sodium carbonate. The mixture was extractedwith ethyl acetate, and the organic phase dried, filtered and evaporatedunder reduced pressure to yield the title compound, bp 88-96/0.05-0.08mm Hg.

B. 2-[(5-Dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamine

To a solution of 2-aminoethanethiol hydrochloride (2.27 g; 20.0 mmoles)in 20 ml of concentrated HCl that was cooled in an ice-salt bath to -10°was added dropwise 5-dimethylaminomethyl-3-methyl-2-furanmethanol (3.38g; 20.0 mmoles) [prepared in Step A], and the mixture stirred for 15minutes then allowed to stand in the cold (0°) overnight. After 17 hoursthe cold solution was made strongly basic with aqueous KOH solution andthen extracted with five portions of methylene chloride. The combinedorganic phase was dried, filtered and evaporated under reduced pressureto yield the title compound (4.16 g), bp 110°-120°/0.1 mm Hg.

C.3-{2-[(5-Dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a methanol suspension of 3,4-dimethoxy1,2,5-thiadiazole 1,1-dioxideis reacted with an equimolar amount of2-[(5-dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamine[prepared in Step B] and the resultant3-{2-[(5-dimethylaminomethyl-3-methyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide is treated with an excess of methylamine, the title compoundis thereby produced.

EXAMPLE 163-{2-[(5-Dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A. 2-Dimethylaminomethyl-3-methylfuran

A stirred solution of 3-methyl-2-furfuryl alcohol 25.2 g; 22.5 mmoles)and triethylamine (27.3 g; 27.0 mmoles) in 200 ml of methylene chloridewas cooled to -15° in an ice-salt bath and a solution of thionylchloride (18.0 ml, 24.8 mmoles) in 30 ml of methylene chloride was addeddropwise, keeping the temperature between -10° to -15°. After 15minutes, the mixture was poured into ice-water and the organic layer wasseparated. The methylene chloride phase containing3-methyl-2-chloromethylfuran was added to a stirred solution, at 0°, ofdimethylamine (137.0 g; 3.04 moles) in 400 ml of absolute ethanol andthe resulting solution was stirred at ambient temperature for 17 hours.The reaction mixture was evaporated under reduced pressure and theresidue was mixed with 400 ml of water, made strongly basic with 40%aqueous NaOH and extracted with five portions of methylene chloride. Thecombined extracts were dried, filtered and evaporated under reducedpressure to yield 26.0 g of the title compound, bp 64°-70°/20 mm Hg. ATLC [Silica/CHCl₃ :CH₃ OH (85:15)] gave Rf=0.50.

B. 2-Chloromethyl-5-dimethylaminomethyl-3-methylfuran

To a solution of 2-dimethylaminomethyl-3-methylfuran (6.5 g; 37.0mmoles) [prepared in Step A] in 250 ml of chloroform was addedparaformaldehyde (1.67 g; 55.7 mmoles) and zinc chloride (312 mg), and aslow stream of HCl gas was bubbled through while stirring at ambienttemperature for 15 minutes. Stirring was continued for 2 hours, then HClgas was bubbled through for 15 minutes and the mixture stirred for 1hour. At this time additional paraformaldehyde (1.67 g; 55.7 mmoles) wasadded to the reaction mixture and a slow stream of HCl gas was passedthrough for 15 minutes. After stirring at ambient temperature for 18hours, the reaction mixture was filtered through Celite and the filtrateevaporated under reduced pressure to yield the title compound (4.97 g)which crystallized upon standing and was used without furtherpurification in Step C.

The NMR spectrum (60 MHz) in CDCl₃ gave the following resonances δ: 6.33(s, 1H), 4.55 (s, 2H); 4.30 (d, 2H); 2.83 (d, 6H); 2.13 (s, 3H)

C. 2-[(5-Dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamine

To a solution of 2-chloromethyl-5-dimethylaminomethyl-3-methylfuran (773mg, 3.45 mmoles) [prepared in Step B] in 20 ml of concentratedhydrochloric acid that was cooled in an ice-water bath was added2-aminoethanethiol hydrochloride (392 mg, 3.45 mmoles), and the mixturewas stirred for 30 minutes. The solution was allowed to stand at 0° for3 days, then made strongly basic with 50% aqueous KOH, diluted withwater and extracted with five portions of methylene chloride. Thecombined extract was dried, filtered and evaporated under reducedpressure to yield the title compound as an oil.

The product was dissolved in absolute ethanol, treated with anhydroushydrogen chloride and evaporated under reduced pressure. The residue wasdissolved in hot isopropyl alcohol, treated with charcoal, filtered andconcentrated to crystallize the hydrochloride salt. Recrystallizationfrom isopropyl alcohol yielded the title compound as the dihydrochloridesalt, mp 185°-190° (dec).

D.3-{2-[(5-Dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is reacted with an equimolar amount of2-[(5-dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamine[prepared in Step C] and the resultant3-{2-[(5-dimethylaminomethyl-4-methyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide is treated with an excess of methylamine, the title compoundis produced.

EXAMPLE 173-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-hydroxy-1,2,5-thiadiazole1,1-dioxide

A.3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-furylmethylthio]ethylamine(2.14 g; 10.0 mmoles) in 25 ml of dry methanol was added dropwise over35 minutes to a well stirred suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1.78 g; 10.0 mmoles) in 180ml of dry methanol that had been cooled to 1° in an ice-water bath.After 15 minutes at 0°, a methanol solution of the title compound isproduced. A TLC [silica/CH₂ Cl₂ :CH₃ OH (9:1)] gave Rf=0.48.

A 2.0 ml aliquot of the solution was made acidic with 6.0 N HCl andevaporated under reduced pressure without heating to yield the titlecompound as the hydrochloride salt. The NMR spectrum (100 MHz) in D₂ Ogave the following resonances δ: 6.45 (d, 1H); 6.19 (d, 1H); 4.14 (s,2H); 4.0 (s, 3H); 3.64 (s, 2H); 3.37 (t, 2H); 2.65 (s, 6H); 2.61 (t,2H).

B.3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-hydroxy-1,2,5-thiadiazole1,1-dioxide

To the methanolic solution of the product of Step A, cooled to 0° in anice-water bath, was added a solution of sodium hydroxide pellets (2.10g; 52.5 mmoles) in 25 ml of dry methanol. After stirring at 0° for 2hours and at ambient temperature for 68 hours, the reaction mixture wasneutralized with 8.75 ml (52.5 mmoles) of aqueous 6.0 N HCl and after 10minutes for stirring was evaporated under reduced pressure. The residuewas crystallized under 95% EtOH to give crude product which wasdissolved in methanol, filtered to remove sodium chloride, placed on 60g of silica gel and chromatographed using a gradient elution ofmethylene chloride-methanol. The appropriate fractions were combined andevaporated under reduced pressure to give 3.19 g of product.Recrystallization from aqueous methanol yielded the title compound, mp109°-122°.

Anal. Calcd for C₁₂ H₁₈ N₄ O₄ S₂ : C, 41.61; H, 5.24; N, 16.17; S,18.51. Found (corr. for 1.15% H₂ O): C, 41.59; H, 5.32; N, 16.33; S,18.81.

EXAMPLE 183-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}4-methylamino-1,2,5-thiadiazole1-oxide

A.3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1-oxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(3.30 g; 15.4 mmoles) in 25 ml of methanol was added dropwise over aperiod of 14 minutes to a well stirred suspension of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.50 g; 15.4 mmoles) [preparedaccording to the procedure in Example 4, Step A] that was cooled to12°-15° in an ice-water bath. The solution was stirred at ambienttemperature for 1.5 hours to yield a methanolic solution of the titlecompound.

B.3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

To the methanolic solution of the product of Step A that was cooled to5° in an ice-water bath was added anhydrous methylamine for 8 minutes.The reaction mixture was stirred at ambient temperature for 17 hours,then evaporated under reduced pressure to give the product as a yellowoil that was placed on 55 g of silica gel and chromatographed using agradient elution of methylene chloride-methanol. The appropriatefraction was evaporated, dissolved in methanol and diluted with diethylether to yield the title compound (2.32 g) as a solid that was dried invacuo at ambient temperature over P₂ O₅ for 3 hours, mp 86°-92°.

Anal. Calcd for C₁₃ H₂₁ N₅ O₂ S₂ : C, 45.46; H, 6.16; N, 20.39; S,18.67. Found: C, 45.24; H, 6.24; N, 20.41; S, 18.90.

EXAMPLE 193-Allylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

To a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide(2.08 g; 11.7 mmoles) in 200 ml of methanol that had been cooled to 0°in an ice-water bath was added dropwise over a period of 45 minutes asolution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine in30 ml of methanol. When the addition was completed, 10.5 ml ofallylamine was added and the solution was allowed to stir at ambienttemperature for 18 hours. The reaction mixture was evaporated underreduced pressure and the residue was placed on 120 g of silica gel andchromatographed using a gradient elution of methylene chloride-methanol.The appropriate fractions were combined, evaporated under reducedpressure and the residue crystallized with isopropyl alcohol to give thetitle compound, mp 83°-86°; the NMR spectrum (100 MHz) in d₆ dimethylsulfoxide showed the presence of approximately 0.9 moles of isopropylalcohol.

Anal. Calcd for C₁₅ H₂₃ N₅ O₃ S₂.0.9C₃ H₈ O: C, 48.36; H, 6.92; N,15.93; S, 14.59. Found: C, 48.46; H, 6.96; N, 16.13; S, 14.58.

EXAMPLE 203-Methylamino-4-{2-[(5-methylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide and3,4-bis-{2-[(5-methylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

A.3-Methylamino-4-{2-[(5-methylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

To a partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole (1.89 g; 10.5mmoles) in 210 ml of methanol that was cooled to 8° was added all atonce a solution of 2-[(5-methylaminomethyl-2-furyl)methylthio]ethylamine(0.7 g; 3.51 mmoles) [prepared according to the procedure described inBelgian Pat. No. 857,388] in 21 ml of methanol. The mixture was stirredfor 15 minutes and cooled to 1° in an ice-water bath, and anhydrousmethylamine then was bubbled into the solution for 6 minutes. Afterstirring for 15 minutes the reaction mixture was evaporated underreduced pressure and the residue placed on 110 g of silica gel using agradient elution from acetonitrile to acetonitrile-methanol-glacialacetic acid (50:50:0.5). The appropriate fractions containing the firsteluting component with Rf=0.50 [TLC-silica/CH₃ CN:CH₃ OH:CH₃ COOH(50:50:1)] were combined and evaporated under reduced pressure to yieldthe title compound as a foam, mp. 50°-56°.

The NMR spectrum (100 MHz) in d₆ dimethyl sulfoxide gave the followingresonances δ: 6.20 (m, 2H); 3.80 (s, 2H); 3.62 (s, 2H); 3.50 (t, 2H);2.90 (s, 3H); 2.70 (t, 2H); 2.28 (s, 3H); it also showed the presence ofapproximately 0.2 mole of methanol.

Anal. Calcd for C₁₂ H₁₉ N₅ O₃ S₂.0.2CH₃ OH: C, 41.65; H, 5.65; N, 19.96;S, 18.28. Found (corr. for 1.42% H₂ O): C, 41.98; H, 5.69; N, 19.54; S,18.54.

B.3,4-Bis-{2-[(5-methylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

The fractions containing the slower eluting component from thechromatography in Step A with Rf=0.07 [TLC-silica/CH₃ CN:CH₃ OH:CH₃ COOH(50:50:1)] were combined, evaporated and the residue partitioned between2.5 N NaOH and ethyl acetate. The aqueous phase was extracted withseveral portions of ethyl acetate and the combined organic layer wasdried and evaporated under reduced pressure to give the title compoundas an oil.

The NMR spectrum (100 MHz) in d₆ dimethyl sulfoxide gave the followingresonances δ: 6.22 (m, 4H); 3.82 (s, 4H); 3.65 (s, 4H); 3.50 (t, 4H);2.72 (t, 4H); 2.30 (s, 6H).

EXAMPLE 213-{4-(5-Dimethylaminomethyl-2-furyl)butylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A solution of 4-(5-dimethylaminomethyl-2-furyl)butylamine (1.5 g; 7.64mmoles) [prepared according to the procedure described in U.S. Pat. No.4,128,658] in 40 ml of dry methanol was added dropwise over a period of45 minutes to a stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (1.36 g; 7.64 mmoles) in 200 ml of dry methanol that hadbeen cooled to 3° in an ice-water bath. After 15 minutes at 3°,anhydrous methylamine was bubbled into the cooled solution for 10minutes. The reaction mixture was evaporated under reduced pressure andthe residue placed on 60 g of silica gel and chromatographed using agradient elution of acetonitrile-methanol. The appropriate fractionswere combined to give 2.16 g of product. Recrystallization fromacetonitrile yielded the title compound, mp 152°-153°.

Anal. Calcd for C₁₄ H₂₃ N₅ O₃ S: C, 49.25; H, 6.79; N, 20.51; S, 9.39.Found: C, 49.41; H, 6.87; N, 20.61; S, 9.28

EXAMPLE 223-{2-[(5-Dimethylaminomethyl-2-furyl)methoxy]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is reacted with one equivalent of2-[(5-dimethylaminomethyl-2-furyl)methoxy]ethylamine [prepared accordingto U.S. Pat. No. 4,128,658] and then with excess methylamine, the titlecompound is thereby produced.

EXAMPLE 233-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-ethylamino-1,2,5-thiadiazole1,1-dioxide

Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide with one equivalent of ethylamine and treatment of theresultant 3-methoxy-4-ethylamino-1,2,5-thiadiazole 1,1-dioxide with oneequivalent of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamineyields the title compound, which is identical to the product prepared inExample 12.

EXAMPLE 243-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

Reaction of a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole1-oxide [prepared in Example 4, Step A] with one equivalent ofmethylamine and treatment of the resultant3-methoxy-4-methylamino-1,2,5-thiadiazole 1-oxide with one equivalent of2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine yields the titlecompound, which is identical to the product prepared in Example 18.

EXAMPLE 253-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A. 3-Methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1,1-dioxide

A solution of 2-aminoethanethiol (from the hydrochloride 1.91 g; 16.8mmoles) in 20 ml of methanol was added dropwise over a period of 15minutes to a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (3.0 g; 16.8 mmoles) in 250 ml of methanol that had beencooled to 1° in an ice-water bath. After 10 minutes at 2°-4°,methylamine was bubbled into the cooled solution for 6 minutes andstirring was continued for an additional 30 minutes at ambienttemperature. The reaction mixture was evaporated under reduced pressureand the residue placed on 45 g of silica gel and chromatographed using agradient elution of methylene chloride-methanol. The appropriatefractions were combined and evaporated, and the product (2.43 g) wascrystallized from absolute ethanol. Recrystallization from absoluteethanol yielded the title compound, mp. 259°-260° (dec).

Anal. Calcd for C₅ H₁₀ N₄ O₂ S₂ : C, 27.03; H, 4.54; N, 25.20. Found: C,27.13; H, 4.55; N, 24.86.

B.3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A mixture containing 3-methylamino-4-(2-mercaptoethyl-1,2,5-thiadiazole1,1-dioxide (1.0 g; 4.5 mmoles) [prepared in Step A] and5-dimethylaminomethyl-2-furanmethanol (0.82 g; 4.5 mmoles) [preparedaccording to the procedure in J. Chem. Soc., 4728 (1958)] in 20 ml ofconcentrated hydrochloric acid was stirred in an ice-water bath for 2hours and then allowed to stand at 0° for 64 hours. The reaction mixturewas stirred at ambient temperature for 23 hours, evaporated withoutheating under reduced pressure and the residue partitioned between waterand methylene chloride. The aqueous phase was made basic with sodiumbicarbonate and extracted with methylene chloride. The combined organicphase was washed with saturated brine solution, dried and evaporatedunder reduced pressure. The residue was placed on 25 g of silica gel andchromatographed using a gradient elution of methylene chloride-methanol.The appropriate fraction was evaporated and the product crystallizedfrom methanol. Recrystallization from methanol yielded the titlecompound, mp 92°-96°.

EXAMPLE 263-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

A. 3-Methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1-oxide

A solution of 2-aminoethanethiol (from the hydrochloride, 2.04 g; 18.0mmoles) in 25 ml of methanol was added dropwise over a period of 30minutes to a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole1-dioxide (2.92 g; 18.0 mmoles) [prepared in Example 4, Step A] in 150ml of methanol that had been cooled to 3° in an ice-water bath. After 10minutes, anhydrous methylamine was bubbled into the solution for 6minutes and stirring was continued at ambient temperature for anadditional 20 minutes. The reaction mixture was evaporated under reducedpressure and the residue placed on 45 g of silica gel andchromatographed using a gradient elution of methylene chloride-methanol.The appropriate fractions were combined and evaporated to give 2.74 g ofproduct. Recrystallization from methanol and then 95% ethanol yieldedthe title compound, mp 191°-193°.

B.3-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

When 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1-oxide[prepared in Step A] is treated with about one equivalent of5-dimethylaminomethyl-2-furanmethanol in concentrated hydrochloric acidaccording to the procedure described in Example 25, Step B, the titlecompound is thereby produced; identical to the product of Example 18.

EXAMPLE 273-{3-[(5-Dimethylaminomethyl-2-furyl)methylthio]propylamino}-4-ethylamino-1,2,5-thiadiazole1,1-dioxide

When 1-phthalimido-3-[(5-dimethylaminomethyl-2-furyl)methylthio]propane[prepared according to the procedure described in Belgian Pat. No.857,388] is treated with hydrazine, and the resulting substitutedpropylamine is reacted according to the general procedure of Example 12,the title product is thereby produced.

EXAMPLE 283-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-dimethylamino-1,2,5-thiadiazole1,1-dioxide

To a cooled (6°) partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (2.08 g; 11.7 mmoles) in 200 ml of methanol was addeddropwise over a period of 45 minutes a solution of2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine (2.5 g; 11.7mmoles) in 50 ml of methanol. When the addition was completed, anhydrousdimethylamine was bubbled into the solution for 10 minutes whilemaintaining the temperature at 6°. After stirring at ambient temperaturefor 18 hours, the reaction mixture was evaporated under reduced pressureand the residue placed on 200 g of silica and chromatographed using agradient elution of methylene chloride-methanol. The appropriatefractions were combined and evaporated and the residue wasrechromatographed on 75 g of aluminum oxide using a gradient elution ofmethylene chloride-methanol. The appropriate fractions were combined andevaporated under reduced pressure to give the title compound, mp139°-142°.

Anal. Calcd for C₁₉ H₂₄ N₅ O₃ S₂ : C, 44.90; H, 6.46; N, 18.70; S,17.12. Found (Corr. for 0.51% H₂ O): C, 44.77; H, 6.25; N, 18.89; S,17.42.

EXAMPLE 29

The general procedure of Example 28 is repeated, except that thedimethylamine utilized therein is replaced by

thiomorpholine,

piperazine,

N-acetylpiperazine,

N-methylpiperazine,

hexamethyleneimine and

homopiperazine, respectively, and there is thereby produced

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(4-thiomorpholinyl)-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(1-piperazinyl)-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(4-acetyl-1-piperazinyl)-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(4-methyl-1-piperazinyl)-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(1-hexamethyleneimino)-1,2,5-thiadiazole1,1-dioxide and

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(1-homopiperazinyl)-1,2,5-thiadiazole1,1-dioxide, respectively.

EXAMPLE 30

The general procedure of Example 13 is repeated, except that the2-propynylamine utilized therein is replaced by an equimolar amount of

cyclobutylamine,

aminomethylcyclobutane,

ethanolamine,

2-methylthioethylamine,

2,2,2-trifluoroethylamine,

2-fluoroethylamine,

ethylenediamine,

2-methylaminoethylamine,

2-dimethylaminoethylamine,

1,1-dimethylhydrazine,

cyanamide,

3-aminopropionitrile,

guanidine and

methylguanidine, respectively, and there is thereby produced

3-(cyclobutylamino)-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide,

3-[(cyclobutyl)methylamino]-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(2-hydroxyethylamino)-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(2-methylthioethylamino)-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(2,2,2-trifluoroethylamino)-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(2-fluoroethylamino)-1,2,5-thiadiazole1,1-dioxide,

3-(2-aminoethylamino)-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(2-methylaminoethylamino)-1,2,5-thiadiazole1,1-dioxide.

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(2-dimethylaminoethylamino)-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(2,2-dimethylhydrazino)-1,2,5-thiadiazole1,1-dioxide,

3-cyanoamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide,

3-(3-cyanopropylamino)-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-guanidino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(N'-methyl)guanidino-1,2,5-thiadiazole1,1-dioxide.

EXAMPLE 313-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (fromthe dihydrochloride, 4.27 g; 14.0 mmoles) in 30 ml of methanol was addedto a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (2.50 g; 14.0 mmoles) in 250 ml of methanol at 10°. After 15minutes at 10°, the solution was cooled to 1° in a cooling bath andanhydrous methylamine was bubbled into the solution for 10 minutes. Thereaction mixture was evaporated under reduced pressure and the residueplaced on 60 g of silica gel and chromatographed using a gradientelution of methylene chloride-methanol. The appropriate fractioncontaining 4.53 g of product was placed on 80 g of aluminum oxide andrechromatographed using a gradient elution of ethyl acetate-methanol.The appropriate fractions were combined and evaporated to give a foamwhich crystallized from methanol to yield (2.38 g) of the titlecompound, mp 196°-198° (dec).

Anal. Calcd for C₁₀ H₁₆ N₈ O₂ S₃ : Cl, 31.90; H, 4.28; N, 29.77; S,25.55. Found: C, 31.85; H, 4.24; N, 29.79; S, 25.45.

EXAMPLE 323-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-(2-propynyl)amino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (fromthe dihydrochloride, 3.42 g; 11.2 mmoles) in 25 ml of methanol was addedto a well stirred cold (8°) suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200ml of methanol. After 15 minutes at 8°-10°, the solution was cooled to1° in an ice-bath and a solution of 6.0 ml 2-propynylamine in 15 ml ofmethanol was added. The ice-bath was removed and stirring was continuedfor 15 minutes. The reaction mixture was evaporated under reducedpressure and the residue placed on 50 g of silica gel andchromatographed using a gradient elution of methylene chloride-methanol.Two of the fractions yielded crystalline product (1.74 g) from methanol.The product was dissolved in hot methanol, filtered through Celite,cooled and filtered to yield the title compound, mp 176°-178°.

Anal. Calcd for C₁₂ H₁₆ N₈ O₂ S₃ : C, 35.99; H, 4.03; N, 27.98; S,24.02. Found: C, 35.82; H, 4.12; N, 28.41; S, 24.28.

EXAMPLE 333-{2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A. N-Carbophenoxy-N-methylaminoacetonitrile

To a suspension of methylaminoacetonitrile hydrochloride (100 g; 0.94mole) in 1 liter of methylene chloride (cooled in an ice-water bath) wasadded triethylamine (260 ml, 1.88 moles) and a solution of phenylchloroformate (155.0 g; 0.99 mole) in 500 ml of methylene chloride. Thereaction mixture was heated at reflux temperature for 18 hours, thenevaporated under reduced pressure to give a semi-solid which wastriturated with 1 liter of diethyl ether and filtered. The filtrate wasevaporated under reduced pressure and the residual oil was vacuumdistilled to yield the title compound (123 g), bp 111°-113°/0.25 mm Hg;the NMR spectrum (60 MHz) in CDCl₃ gave the following resonances δ: 7.23(m, 5H); 4.30 (s, 2H); 3.13 (s, 3H).

B. (N-Carbophenoxy-N-methylamino)thioacetamide

A solution of N-carbophenoxy-N-methylaminoacetonitrile (131.0 g; 0.69mole) [prepared in Step A] and thioacetamide (57.1 g; 0.71 mole) in 917ml of dry DMF was treated with HCl gas until an exothermic reaction tookplace, and then heated on a steam bath for 20 minutes. The reactionmixture was partially evaporated under reduced pressure to remove someof the solvent, then made basic with saturated aqueous NaHCO₃ solutionand partitioned between ether and water. The aqueous phase was extractedwith ether and the combined ether phase was washed with water, saturatedaqueous NaCL solution and dried. Filtration and evaporation of thesolvent gave an oil which was triturated with methylcyclohexane to givethe product as a solid. Recrystallization from isopropyl alcohol yieldedthe title compound, mp 101°-103°.

Anal. Calcd C₁₀ H₁₂ N₂ O₂ S: C, 53.55; H, 5.40; N, 12.49; S, 14.30.Found: C, 53.65; H, 5.51; N, 12.69; S, 14.41.

C. 4-Chloromethyl-2-(N-carbophenoxy-N-methylamino)methylthiazole

To a cooled solution of (N-carbophenoxy-N-methylamino)thioacetamide (1.0g; 4.46 mmoles) and dry pyridine (0.36 ml, 4.46 mmoles) in 6 ml ofabsolute ethanol was added a solution of 1,3-dichloropropanone (0.57 g;4.49 mmoles) in 3 ml of absolute ethanol. The mixture was heated atreflux temperature for 1.5 hours, then evaporated under reduced pressureand the oil residue partitioned between ether and water. The aqueouslayer was extracted with ether and the combined ether phase was washedwith water, saturated aqueous sodium chloride solution and dried.Filtration and evaporation yielded 1.02 g of the title compound as aviscous oil; TLC [silica/CH₂ Cl₂ :CH₃ CN (85:15)] gave Rf=0.82. The NMRspectrum (60 MHz) in CDCl₃ gave the following resonances δ: 7.16 (m,6H); 4.77 (broad s, 2H); 4.60 (s, 2H); 3.07 (broad s, 3H).

D.2-{[2-(N-Carbophenoxy-N-methylamino)methyl-4-thiazolyl]methylthio}ethylamine

To a solution of sodium methoxide (26.1 g; 0.48 mole) in 290 ml ofabsolute ethanol at 0° under a nitrogen atmosphere was added crysteaminehydrochloride (27.6 g; 0.24 mole) and an additional 218 ml of absoluteethanol. After stirring at 0° for 1 hour a solution of4-chloromethyl-2-(N-carbophenoxy-N-methylamino)methylthiazole (72.5 g;0.24 mole) in 218 ml of absolute ethanol was added over a 15 minuteperiod. The reaction mixture was stirred at ambient temperature for 18hours, filtered and evaporated under reduced pressure to give an oilwhich was partitioned between methylene chloride and water. The aqueousphase was extracted with methylene chloride and the combined organicphase was washed with water, dried, filtered and evaporated underreduced pressure to give the product (68.5 g) as an oil which wastreated with fumaric acid (23.6 g) in n-propanol to give the salt (47.0g). Recrystallization from absolute ethanol yielded the title compoundas the fumarate salt, mp 145° -146°.

Anal. Calcd for C₁₅ H₁₉ N₃ O₂ S₂.C₄ H₄ O₄ : C, 50.31; H, 5.11; N, 9.27;S, 14.14. Found: C, 50.02; H, 5.16; N, 9.47; S, 14.22.

E. 2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine

To a solution of2-{[2-(N-Carbophenoxy-N-methylamino)methyl-4-thiazolyl]methylthio}ethylamine(0.50 g; 1.48 mmoles) [prepared in Step D] in 10 ml of drytetrahydrofuran under a nitrogen atmosphere was added lithium aluminumhydride (0.17 g; 4.48 mmoles) and the mixture was heated at refluxtemperature for 0.5 hour. An additional 10 ml of tetrahydrofuran wasadded and heating was continued for 3 hours. The reaction mixture wastreated with 0.17 ml of H₂ O, 0.17 ml of 15% aqueous NaOH and 0.51 ml ofH₂ O, and filtered through Celite and dried. The filtrate was filteredand evaporated under reduced pressure to give an oil which was dissolvedin absolute ethanol, diluted with diethyl ether and acidified with dryHCl. The hydroscopic hydrochloride salt of the title compound wascollected and partitioned between aqueous 2.5 N NaOH and methylenechloride. The organic phase was washed with water, dried and filtered.The filtrate was evaporated under reduced pressure to give the free baseof the title compound as an oil (0.22 g; 0.95 mmole) which was combinedwith anhydrous oxalic acid (0.24 g; 1.90 mmole) in 30 ml of hotacetonitrile. The mixture was evaporated from hot absolute ethanol toyield the title compound the bis-oxalate, mp 168°-171°.

Anal. Calcd for C₉ H₁₇ N₃ O₄ S₂.2C₂ H₂ O₄ : C, 37.95; H, 5.15; N, 10.21;S, 15.59. Found: C, 37.95; H, 5.04; N, 9.81; S, 15.27.

F.3-{2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

To a cooled (6°) suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (0.74 g; 4.17 mmoles) in 80 ml of methanol was addeddropwise over a period of 45 minutes a solution of2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine (0.96 g;4.17 mmoles) [prepared in Step E] to give3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide, Rf=0.64 [Silica/CH₂ Cl₂ :CH₃ OH (9:1)]. The temperature wasmaintained at 6° and anhydrous methylamine was bubbled into the solutionfor 8 minutes. The reaction mixture was evaporated under reducedpressure and the residue placed on 80 g of silica gel andchromatographed using a gradient elution of methylene chloride-methanol.The appropriate fractions were combined and the residue wasrechromatographed on 25 g of aluminum oxide using a gradient elution ofmethylene chloride-methanol to give 0.52 g of product. Recrystallizationfrom isopropyl alcohol/ether yielded the title compound, mp 144°-148°(foaming).

Anal. Calcd for C₁₂ H₂₀ N₆ O₂ S₃ : C, 38.28; H, 5.35; N, 22.32; S,25.55. Found: C, 37.89; H, 5.43; N, 22.19; S, 25.40.

EXAMPLE 343-{2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

A. N-Carbethoxy-N-methylaminoacetonitrile

Triethylamine (5.2 ml; 37.6 mmoles) was added to a suspension ofmethylaminoacetonitrile hydrochloride (2.0 g; 18.8 mmoles) in 20 ml ofmethylene chloride. The resulting suspension was cooled in an ice-bathand a solution of ethyl chloroformate (2.14 g; 19.8 mmoles) in 10 ml ofmethylene chloride was added over a 0.5 hour period, and the mixture wasthen heated at reflux temperature for 18 hours. The reaction mixture wasevaporated under reduced pressure to give a semi-solid residue which wastriturated with diethyl ether and filtered, and the filtrate wasevaporated under reduced pressure to yield the title compound as an oil(2.2 g), bp 96°-98°/5.2 mm Hg.

B. (N-Carbethoxy-N-methylamino)thioacetamide

A solution of N-carbethoxy-N-methylaminoacetonitrile (9.8 g; 6.9 mmoles)[prepared in Step A], and thioacetamide (10.35 g; 13.8 mmoles) in 175 mlof dry DMF was treated with hydrogen chloride gas until a vigorousexothermic reaction took place, and then was heated on a steam bath for15 minutes. The reaction mixture was made basic with saturated NaHCO₃solution, and then extracted with ether, washed with water and dried.The etheral phase was evaporated under reduced pressure to give a solidresidue which was dissolved in methylene chloride and washed with water.The organic phase was dried, filtered and evaporated under reducedpressure to give product (2.5 g). Recrystallization from ethylacetate-hexane yielded the title compound, mp 91°-93°.

Anal Calcd for C₆ H₁₂ N₂ O₂ S: C, 40.89; H, 6.87; N, 15.96; S, 18.92.Found: C, 40.73; H, 6.85; N, 16.13; S, 18.86.

C. 2-(N-Carbethoxy-N-methylamino)methyl-4-carbethoxythiazole

To a solution of (N-carbethoxy-N-methylamino)thioacetamide (30.7 g; 0.17mole) [prepared in Step B] in 180 ml of absolute ethanol was added asolution of ethyl bromopyruvate (25.0 ml; 0.20 mole) in 130 ml ofabsolute ethanol. The reaction mixture was heated at reflux temperaturefor 17 hours and then evaporated under reduced pressure, and the residuewas partitioned between ether and water. The organic layer was washedwith water and saturated sodium chloride solution, dried, filtered andevaporated under reduced pressure to give an oil which was placed onsilica gel and chromatographed using diethyl ether as the elutingsolvent. The appropriate fractions yielded the title compound as an oil;TLC [Silica/CH₂ Cl₂ :CH₃ CN (85.15)] gave Rf=0.50. The NMR spectrum (60MHz) in d₆ dimethyl sulfoxide gave the following resonances δ: 8.49 (s,1H); 4.79 (s, 2H); 4.23 (m, 4H); 3.00 (s, 3H); 1.30 (q, 6H).

D. 2-Dimethylaminomethyl-4-hydroxymethylthiazole

To a cooled suspension of lithium aluminum hydride (8.4 g; 0.22 mole) in80 ml of dry tetrahydrofuran was added a solution of2-(N-carbethoxy-N-methylamino)methyl-4-carbethoxythiazole (20.0 g; 0.07mole) [prepared in Step C] in 160 ml of dry tetrahydrofuran over a 1hour period. The reaction mixture was heated at reflux temperature for 8hours, then cooled and decomposed with Na₂ SO₄ and 40% aqueous potassiumhydroxide. The mixture was filtered, dried and evaporated under reducedpressure to give 4.2 g of the title compound as an oil; TLC (aluminumoxide/CH₃ CN) gave RF=0.45. The NMR spectrum (60 MHz) in CDCl₃ gave thefollowing resonances δ: 7.17 (s, 1H); 4.73 (d, 2H); 3.43 (s, 2H); 3.35(s, 6H).

E. 2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine

When 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Step D]is reacted with thionyl chloride and the resultant2-dimethylaminomethyl-4-chloromethylthiazole is reacted with anequimolar amount of cysteamine hydrochloride and two equivalents of baseaccording to the general procedure of Example 33, Step D, the titlecompound is thereby produced.

F.3-{2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

When a methanol suspension of 3,4-dimethoxy-1,2,5-thiaziazole 1-oxide[prepared in Example 4, Step A] is reacted with an equimolar amount of2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared inExample 33, Step E] and the resulting3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1-oxide is treated with methylamine, the title compound is therebyproduced.

EXAMPLE 353-Amino-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (2.75 g;11.9 mmoles) [obtained by neutralization of2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine dihydrochloride (4.0g; 13.0 mmoles) with 2.5 N aqueous sodium hydroxide and extraction withethyl acetate]in 30 ml of methanol was added over a 1 hour period to awell stirred, cold (0°) suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (2.12 g; 11.9 mmoles) in 220 ml of methanol. Whilemaintaining the temperature at 0°, anhydrous ammonia was bubbled intothe solution for 6 minutes and stirring was continued at ambienttemperature for 0.5 hour. The reaction mixture was evaporated underreduced pressure and the residue placed on 120 g of silica gel andchromatographed using a gradient elution of methylene chloride-methanol.The appropriate fractions were combined and evaporated, and the residuewas rechromatographed on 40 g of silica gel using a gradient elution ofmethylene chloride-methanol. The appropriate fractions were combined,concentrated under vacuum, filtered and dried under high vacuum to yieldthe title compound, mp 134°-149° (foaming); the NMR spectrum (100 MHz)in d₆ dimethyl sulfoxide/D₂ O/DCl gave the following resonances δ: 7.16(s, 1H); 3.84 (s, 2H); 3.52 (t, 2H); 2.75 (t, 2H); and showed thepresence of approximately 1.2 moles of methanol.

Anal. Calcd for C₉ H₁₄ N₈ O₂ S₃.1.2CH₃ OH: C, 30.56; H, 4.72; N, 27.95;S, 23.99. Found (corr. for 1.31% H₂): C, 30.19; H, 4.32; N, 27.91; S,24.71.

EXAMPLE 363-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-(2-hydroxyethylamino)-1,2,5-thiadiazole1,1-dioxide

To a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (2.05 g; 11.5 mmoles) in 200 ml of dry methanol at 3° wasadded, dropwise over 30 minutes, a solution of2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (from thedihydrochloride; 3.5 g; 11.5 mmoles) in 40 ml of dry methanol. After 15minutes at 3°, a solution of ethanolamine (1.03 ml, 17.3 mmoles) in 10ml of methanol was rapidly added dropwise and stirred for 15 minutes.The reaction mixture was evaporated under reduced pressure to give theproduct as a friable foam that crystallized from methanol. Tworecrystallizations from methanol yielded the title compound, mp=slowlyresinified starting at 115°, decomposed starting at 175°.

Anal. Calcd for C₁₁ H₁₈ N₈ O₃ S₃ : C, 32.50; H, 4.46; N, 27.57; S,23.66. Found (corr. for 3.85% H₂ O): C, 32.77; H, 4.21; N, 27.90; S,24.39.

EXAMPLE 373-(2,3-Dihydroxypropylamino)-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine is reacted with3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide by the procedure of Example31 and the resultant3-methoxy-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide is treated with 3-amino-1,2-propanediol, the title compoundis thereby produced.

EXAMPLE 383-Methylamino-4-{2-[(thiazol-2-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of 2-[(thiazol-2-yl)methylthio]ethylamine[prepared according to the procedure described in U.S. Pat. No.3,950,333] is reacted with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxideand the resultant3-methoxy-4-{2-[(thiazol-2-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide treated with methylamine according to the general proceduredescribed in Example 31, the title compound is thereby produced.

EXAMPLE 39

When 2-chloromethyl-4-methylthiazole [prepared by the reaction ofthionyl chloride and 2-hydroxymethyl-4-methylthiazole, which itself isprepared according to the procedure of J. Chem. Soc., (Suppl. Issue No.1), S106-111 (1966) or Acta Chem.Scand., 20, 2649 (1966)] is reactedwith cysteamine hydrochloride and about two equivalents of a strong basesuch as sodium methoxide, and the resultant amine is treated with3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide, there is produced3-methoxy-4-{2-[(4-methylthiazol-2-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide. When the latter compound is reacted with methylamineaccording to the general procedure of Example 31, there is produced3-methylamino-4-{2-[(4-methylthiazol-2-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide.

When the above procedure is repeated, except that the2-chloromethyl-4-methylthiazole utilized therein is replaced by anequimolar amount of the chloromethylthiazoles prepared by reactingthionyl chloride with

2-amino-4-hydroxymethylthiazole¹,

2-hydroxymethyl-4,5-dimethylthiazole²,

4-hydroxymethyl-2-methylthiazole³,

4-hydroxymethyl-2-chlorothiazole⁴,

5-hydroxymethyl-2-methylthiazole⁵,

5-hydroxymethyl-4-methylthiazole⁶,

4-hydroxymethylthiazole⁷ and

4-dimethylaminomethyl-2-hydroxymethylthiazole⁸, respectively, there isthereby produced

3-{2-[(2-aminothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(4,5-dimethylthiazol-2-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(2-methylthiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(2-chlorothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(2-methylthiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(4-methylthiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(thiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide and

3-{2-[(4-dimethylaminomethylthiazol-2-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide, respectively.

The above starting materials are prepared according to the proceduresdescribed in the following publications:

(1) J. Am. Chem. Soc., 68, 2155 (1946);

(2) Helv. Chim. Acta, 31, 652 (1948);

(3) and (5) Zh. Obshch. Khim., 32, 570 (1962) [C. A., 58, 2525b (1963)];

(4) Rev. Roumaine Chim., 10, 897 (1965) [C. A., 64, 8164b (1966)];

(6) J. Am. Chem. Soc., 67, 400 (1945);

(7) Zh. Obshch. Khim., 27, 726 (1957) [C. A., 51, 16436h (1957)];

(8) An ethanol solution of dimethylamine is reacted with2-bromo-4-chloromethylthiazole, prepared according to reference (4)above, and the resultant 2-bromo-4-dimethylaminomethylthiazole istreated with a strong base and formaldehyde according to the generalprocedure described in Acta. Chem. Scand., 20, 2649 (1966), to give thedesired 4-dimethylaminomethyl-2-hydroxymethylthiazole.

EXAMPLE 403-{3-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]propylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example34, Step D] is reacted with 3-mercaptopropylamine hydrochloride[prepared according to the procedure described in J. Org. Chem., 27,2846 (1962)] in aqueous hydrobromic acid (48%), and the resultant amineis successively treated with 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxideand excess methylamine as in the general procedure of Example 31, thetitle compound is produced.

EXAMPLE 413-{2-[(2-Guanidinothiazol-4-yl)methylthio]propylamino}-4-amino-1,2,5-thiadiazole1-oxide

When a methanolic solution of2-[(guanidinothiazol-4-yl)methylthio]propylamine is reacted with3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared in Example 4, Step A],and the resultant3-{2-[(2-guanidinothiazol-4-yl)methylthio]propylamino}-4-methoxy-1,2,5-thiadiazole1-oxide is treated with excess ammonia by the procedure in Example 35,the title compound is thereby produced.

EXAMPLE 423-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide with one equivalent of methylamine and treatment of theresultant 3-methoxy-4-methylamino-1,2,5-thiadiazole 1,1-dioxide with oneequivalent of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine yieldsthe title compound, which is identical to the product obtained inExample 31.

EXAMPLE 433-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a solution of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole1,1-dioxide [prepared in Example 25, Step A] is reacted with4-chloromethyl-2-guanidinothiazole hydrochloride and a strong base, thetitle compound is thereby produced, which is identical to the productobtained in Example 31.

EXAMPLE 443-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-hydroxy-1,2,5-thiadiazole1,1-dioxide

When 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is reacted with oneequivalent of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine and theresultant3-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide is reacted with sodium hydroxide according to the proceduredescribed in Example 17, Step B, the title compound is produced.

EXAMPLE 453-{2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide with one equivalent of methylamine and treatment of theresultant 3-methoxy-4-methylamino-1,2,5-thiadiazole 1,1-dioxide with oneequivalent of2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared inExample 33, Step E], produces the title compound which is identical tothe product prepared in Example 33.

EXAMPLE 463-{2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

Reaction of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole1,1-dioxide [prepared in Example 25, Step A] with about one equivalentof 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example34, Step D] in concentrated hydrochloric acid, and then made basic andworked up, produces the title compound which is identical to the productprepared in Example 33.

EXAMPLE 473-{2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-hydroxy-1,2,5-thiadiazole1,1-dioxide

When a solution of3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide [prepared according to the procedure described in Example33, Step F] is reacted with sodium hydroxide according to the proceduredescribed in Example 17, Step B, the title compound is produced.

EXAMPLE 483-Amino-4-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

When a methanolic solution of3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1-oxide [prepared from 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide by thegeneral procedure described in Example 34, Step F] is reacted withanhydrous ammonia according to the general procedure described inExample 35, the title compound is thereby produced.

EXAMPLE 493-{2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

Reaction of 3-methylamino-4-(2-mercaptoethyl)-1,2,5-thiadiazole 1-oxide[prepared by reacting 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide with2-aminoethanethiol and methylamine according to the procedure describedin Example 25, Step A] with about one equivalent of2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example 34,Step D], produces the title compound.

EXAMPLE 503-Amino-4-[4-(2-guanidinothiazol-4-yl)butylamino]-1,2,5-thiadiazole1-oxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide issuccessively treated with 4-(2-guanidinothiazol-4-yl)butylamine[prepared according to the procedure described in U.S. Pat. No.4,165,377] and excess anhydrous ammonia according to the generalprocedure described in Example 35, the title compound is therebyproduced.

EXAMPLE 513-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio[ethylamino}-4-hydrazino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(2.41 g; 11.2 mmoles) in 30 ml of dry methanol was added dropwise over aperiod of 45 minutes to a well stirred cold (ice-water bath) suspensionof 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in250 ml of methanol. After stirring at 0° for 15 minutes, a solution ofanhydrous hydrazine (1.8 g; 56.13 mmoles) in 30 ml of dry methanol wasadded all at once, and stirring was continued for 30 minutes. Thereaction mixture was evaporated under reduced pressure and the solidresidue was treated with chloroform and filtered to give 3.28 g of thetitle compound, mp 170° (dec.).

EXAMPLE 523-Methylamino-4-{2-[(2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(2-pyridyl)methylthio]ethylamine (from thedihydrobromide, 3.5 g; 10.6 mmoles) [prepared according to the proceduredescribed in Belgian Pat. No. 779,775] in 25 ml of dry methanol wasadded dropwise over 30 minutes to a well stirred suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide in 200 ml of dry methanolthat was cooled to 0°-5° in an ice-water bath. After stirring the coldsolution for 15 minutes, anhydrous methylamine was bubbled into thesolution for 15 minutes. The reaction mixture was stirred at ambienttemperature for 45 minutes, evaporated under reduced pressure and theresidue crystallized with methanol. Two recrystallizations from methanolyielded the title compound, mp 168°-171°.

Anal. Calcd for C₁₁ H₁₅ N₅ O₂ S₂ : C, 42.15; H, 4.82; N, 22.35; S,20.46. Found: C, 42.07; H, 4.75; N, 22.28; S, 20.73.

EXAMPLE 533-{2-[(3-Chloro-2pyridyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is successively treated with2-[(3-chloro-2-pyridyl)methylthio]ethylamine [prepared according to theprocedure described in U.S. Pat. No. 4,024,260] and methylamineaccording to the general procedure of Example 52, the title compound isthereby produced.

EXAMPLE 543-{2-[(6-Dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is successively treated with an equimolar amount of2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamine [prepared inExample 136, Step C] and excess methylamine, the title compound isthereby produced.

EXAMPLE 55

The general procedure of Example 52 is repeated except that the2-[(2-pyridyl)methylthio]ethylamine utilized therein is replaced by anequimolar amount of

2-[(3-bromo-2-pyridyl)methylthio]ethylamine,

2-[(3-cyano-2-pyridyl)methylthio]ethylamine,

2-[(3-hydroxy-2-pyridyl)methylthio]ethylamine,

2-[(3-methoxy-2-pyridyl)methylthio]ethylamine,

2-[(3-ethoxy-2-pyridyl)methylthio]ethylamine,

2-[(3-methyl-2-pyridyl)methylthio]ethylamine and

2-[(3-amino-2-pyridyl)methylthio]ethylamine, respectively,

[prepared according to the general procedures described in Belgian Pat.Nos. 779,775, 804,144 and 844,504] and there is thereby produced

3-{2-[(3-bromo-2-pyridyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(3-cyano-2-pyridyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(3-hydroxy-2-pyridyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(3-methoxy-2-pyridyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(3-ethoxy-2-pyridyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(3-methyl-2-pyridyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide and

3-{2-[(3-amino-2-pyridyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide, respectively.

EXAMPLE 563-{2-[(3-Chloro-2-pyridyl)methylthio]ethylamino}-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is successively treated with2-[(5-dimethylaminomethyl-2furyl)methylthio]ethylamine and2-[(3-chloro-2-pyridyl)methylthio]ethylamine, the title compound isthereby produced.

EXAMPLE 573-{2-[(6-Dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide[obtained from Example 4, Step A] is successively treated with anequimolar amount of2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamine [prepared inExample 136, Step C] and an excess of methylamine, the title compound isthereby produced.

EXAMPLE 583-{2-[(4-Methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A. 3-Hydroxymethyl-4-methylfurazan

To a stirred solution of 3-methyl-4-furazancarboxylic acid (27.0 g; 0.21mole) in 180 ml of tetrahydrofuran (that was cooled in an ice-waterbath) under a nitrogen atmosphere was added dropwise a 1.02 M solutionof borane in tetrahydrofuran (825 ml; 0.84 mole). When the addition wascompleted, the mixture was stirred at ambient temperature overnight.After 20 hours, 6 N HCl was added dropwise until the evolution ofhydrogen ceased and the reaction mixture was evaporated under reducedpressure. The residue was partitioned between methylene chloride andwater, made basic with potassium carbonate and the combined methylenechloride extract was dried and evaporated under reduced pressure to give21.0 g of product. Vacuum distillation yielded the title compound, bp99°/1 mm Hg.

B. 2-[(4-Methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamine

A solution of 3-hydroxymethyl-4-methylfurazan (2.49 g; 21.8 mmoles)[prepared in Step A] and 2-aminoethanethiol hydrochloride (2.48 g; 21.8mmoles) in 60 ml of 48% aqueous hydrobromic acid was stirred and heatedat reflux temperature for 23 hours and then at ambient temperature for40 hours. The excess hydrobromic acid was removed under reducedpressure, and the oil residue was dissolved in isopropyl alcohol,filtered though Celite and the product was crystallized from thefiltrate. Recrystallization from isopropyl alcohol yielded the titlecompound as the hydrobromide salt, mp 142°-143°.

C.3-{2-[(4-Methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is successively treated with an equimolar amount of2-[(4-methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamine [prepared inStep B] and excess methylamine by the general procedure of Example 2,the title compound is thereby produced.

EXAMPLE 593-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-{2-[(4-methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is treated with2-[(4-methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamine [prepared inExample 58, Step B] and2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine, the titlecompound is thereby produced.

EXAMPLE 603-{2-[(5-Methyl-1,2,4-oxadiazol-3-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A. 2-[(5-Methyl-1,2,4-oxadiazol-3-yl)methylthio]ethylamine

Cysteamine hydrochloride (3.03 g; 26.7 mmoles) was added in severalportions over a period of 10 minutes to a stirred solution of sodiummethylate (2.89 g; 53.4 mmoles) in 50 ml of methanol at 0°. Afterstirring for 70 minutes at 0°, a solution of3-chloromethyl-5-methyl-1,2,4-oxadiazole (3.54 g; 26.7 mmoles) in 15 mlof methanol was added dropwise over a period of 15 minutes, and thereaction mixture was allowed to stir at ambient temperature for 16hours. The mixture was filtered, evaporated and redissolved in isopropylalcohol, then filtered and evaporated under reduced pressure to give thetitle compound (5.64 g) as a yellow oil. The NMR spectrum (60 MHz) inCDCl₃ gave the following resonances δ: 3.77 (s, 2H); 2.77 (m, 4H); 2.63(s, 3H).

B.3-{2-[(5-Methyl-1,2,4-oxadiazol-3yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is treated successively with2-[(5-methyl-1,2,4-oxadiazol-3-yl)methylthio]ethylamine [prepared inStep A] and methylamine, by the general procedure of Example 2, thetitle compound is thereby produced.

EXAMPLE 613-{2-[(2-Methyl-1,3,4-oxadiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A. 2-[(2-Methyl-1,3,4-oxadiazol-5-yl)methylthio]ethylamine

Cysteamine hydrochloride (1.13 g; 0.01 mole) was added to a stirredsolution of sodium methylate (1.08 g; 0.02 mole) in 20 ml of methanol at0° under an argon atmosphere. The mixture was stirred for 1 hour at 0°and the resultant suspension was added dropwise over a period of 25minutes to a stirred solution of2-methyl-5-chloromethyl-1,3,4-oxadiazole (1.32 g; 0.01 mole) [preparedby the procedure described in Hel. Chim. Acta, 55, 1979 (1972)] in 15 mlof methanol at 0°. The reaction mixture was stirred at ambienttemperature for 45 minutes, concentrated to near dryness, and thendiluted with methylene chloride, filtered and evaporated under reducedpressure to give the title compound (1.92 g) as a yellow oil. The NMRspectrum (60 MHz) in CDCl₃ gave the following resonances δ: 3.87 (s,2H); 2.8 (m, 4H); 2.53 (s, 3H).

B.3-{2-[(2-Methyl-1,3,4-oxadiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide istreated with an equimolar amount of2-[(2-methyl-1,3,4-oxadiazol-5-yl)methylthio]ethylamine [prepared inStep A] and an excess of methylamine by the general procedure describedin Example 2, the title compound is thereby produced.

EXAMPLE 623-{2-[(2-Dimethylamino-1,3,4-oxadiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When 2-dimethylamino-5-ethoxycarbonyl-1,3,4-oxadiazole [preparedaccording to the procedure described in Org. Magn. Resonance, 6, 144(1974)] is hydrolyzed and reduced with borane as described in Example58, Step A, and then is reacted with cysteamine according to theprocedure described in Example 60, Step A, there is produced2-[(2-dimethylamino-1,3,4-oxadiazol-5-yl)methylthio]ethylamine.

When the above amine is reacted with an equimolar amount of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide, and the resultant3-{2-[(2-dimethylamino-1,3,4-oxadiazol-5-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide is treated with an excess of methylamine, the title compoundis thereby produced.

EXAMPLE 633-{2-[(3-{Dimethylaminomethyl}phenyl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole1,1-dioxide

When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is successively treated with an equimolar amount of2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamine [preparedaccording to the procedure described in Belgian Pat. No. 867,106] andexcess ammonia by the general procedure described in Example 35, thetitle compound is thereby produced.

EXAMPLE 643-{3-[3-(Dimethylaminomethyl)phenoxy]propylamino}-4-amino-1,2,5-thiadiazole1,1-dioxide

When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is successively treated with an equimolar amount of3-[3-(dimethylaminomethyl)phenoxy]propylamine [prepared according to theprocedure described in Belgian Pat. No. 867,106] and excess ammonia bythe general procedure described in Example 35, the title compound isthereby produced.

EXAMPLE 653-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine(1.0 g; 4.34 mmoles) [prepared according to the procedure described inBelgian Pat. No. 867,105] in 25 ml of dry methanol was added dropwiseover a period of 35 minutes to a stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (0.77 g; 4.34 mmoles) in 150ml of dry methanol that had been cooled to 0°-3° in an ice-water bath.After the addition was completed, anhydrous methylamine was bubbled intothe solution for 10 minutes and stirring was continued for 15 minutes.The reaction mixture was evaporated under reduced pressure and theresidue placed on 50 g of silica gel and chromatographed using agradient elution of acetonitrile-methanol. The appropriate fractionswere combined to give 1.0 g of product. Recrystallization from methanolyielded the title compound, mp 60.5°-66°.

EXAMPLE 663-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-ethylamino-1,2,5-thiadiazole1-oxide

When a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared inExample 4, Step A] is successively reacted with an equimolar amount of2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine and excessethylamine according to the procedure described in Example 18, the titlecompound is thereby produced.

EXAMPLE 673-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-{2-[(4-methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide isreacted with an equimolar amount of2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine and theresultant3-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide is treated with2-[(4-methyl-1,2,5-oxadiazol-3-yl)methylthio]ethylamine [prepared inExample 58, Step B], the title compound is thereby produced.

EXAMPLE 683-{4-[(2-Guanidino-4-oxazolyl]butylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide isreacted with an equimolar amount of4-[(2-guanidino-4-oxazolyl]butylamine [prepared according to theprocedure described in Belgian Pat. No. 866,155] and the resultant3-{4-[(2-guanidino-4-oxazolyl]butylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide is treated with excess methylamine, the title compound isthereby produced.

EXAMPLE 693-{2-[(2-(2-Amino-5-oxazolyl)ethylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

Reacting an equimolar amount of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide and 2-[2-(2-amino-5-oxazolyl)ethylthio]ethylamine [preparedaccording to U.S. Pat. No. 3,950,353] and treatment of the resultant3-{2-[2-(2-amino-5-oxazolyl)ethylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide with excess methylamine gives the title compound.

EXAMPLE 703-{2-[3-Isoxazolylmethylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

Reaction of a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide with one equivalent of 2-[3-isoxazolylmethylthio]ethylamine[prepared according to the procedure described in U.S. Pat. No.3,950,353] and treatment of the resultant3-{2-[3-isoxazolylmethylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide with an excess of methylamine, produced the title compound.

EXAMPLE 71

The general procedure of Example 70 is repeated except that the2-[3-isoxazolylmethylthio]ethylamine utilized therein is replaced by anequimolar amount of

2-[(5-methyl-3-isoxazolyl)methylthio]ethylamine,

2-[(3,5-dimethyl-4-isoxazolyl)methylthio]ethylamine and

2-[(2-(5-methyl-4-isoxazolyl)ethylthio]ethylamine, respectively, [eachprepared by the general procedure described in U.S. Pat. No. 3,950,353]and there is thereby produced

3-{2-[(5-methyl-3-isoxazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(3,5-dimethyl-4-isoxazolyl)methylthio}-4-methylamino-1,2,5-thiadiazole1,1-dioxide and

3-{2-[2-(5-methyl-4-isoxazolyl)ethylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide, respectively.

EXAMPLE 723-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-{2-[3-isoxazolylmethylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is reacted with one equivalent of2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine according to theprocedure described in Example 17, Step A, and the resultant product istreated with one equivalent of 2-[(3-isoxazolylmethylthio]ethylamine,the title compound is thereby produced.

EXAMPLE 733-{2-[3-Isothiazolylmethylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

Reaction of a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide with one equivalent of2-[3-isothiazolylmethylthio]ethylamine [prepared according to theprocedure described in U.S. Pat. No. 3,950,353] and treatment of theresultant3-{2-[3-isothiazolylmethylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide with an excess of methylamine, produces the title compound.

EXAMPLE 74

The general procedure of Example 73 is repeated except that the2-[3-isothiazolylmethylthio]ethylamine utilized therein is replaced byan equimolar amount of

2-[(3-methyl-4-isothiazolyl)methylthio]ethylamine,

2-[(4-bromo-3-methyl-5-isothiazolyl)methylthio]ethylamine and

2-[(3-methyl-5-isothiazolyl)methylthio]ethylamine, respectively,[prepared by the general procedures described in U.S. Pat. No. 3,450,353and J. Chem. Soc., 2032 (1963)] and there is thereby produced

3-{2-[(3-methyl-4-isothiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(4-bromo-3-methyl-5-isothiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide and

3-{2-[(3-methyl-5-isothiazolyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide, respectively.

EXAMPLE 753-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-{2-[3-isothiazolylmethylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is reacted with one equivalent of2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine according to theprocedure described in Example 17, Step A, and the resultant3-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide is treated with one equivalent of2-[3-isothiazolylmethylthio]ethylamine, the title compound is produced.

EXAMPLE 763-{2-[(2-Amino-1,3,4-thiadiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

Reaction of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with oneequivalent of 2-[(2-amino-1,3,4-thiadiazol-5-yl)methylthio]ethylamine[prepared according to the procedure described in U.S. Pat. No.3,950,353] and treatment of the resultant3-{2-[(2-amino-1,3,4-thiadiazol-5-yl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1,1-dioxide with methylamine, produced the title compound.

EXAMPLE 77

The general procedure of Example 76 is repeated except that the2-[(2-amino-1,3,4-thiadiazol-5-yl)methylthio]ethylamine utilized thereinis replaced by an equimolar amount of

3-[1,2,4-thiadiazol-3-ylthio]propylamine,

2-[(1,2,3-thiadiazol-4-yl)methylthio]ethylamine,

2-[(3-hydroxy-1,2,5-thiadiazol-4-yl)methylthio]ethylamine and

2-[(3-amino-1,2,5-thiadiazol-4-yl)methylthio]ethylamine, respectively,[prepared by the general procedures described in U.S. Pat. No.3,950,353, J. Am. Chem. Soc., 86, 2861 (1964) and J. Org. Chem., 28,1491 (1963)] and there is thereby produced

3-{3-[1,2,4-thiadiazol-3-ylthio]propylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(1,2,3-thiadiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(3-hydroxy-1,2,5-thiadiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide and

3-{2-[(3-amino-1,2,5-thiadiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide, respectively.

EXAMPLE 783-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-{2-[(3-hydroxy-1,2,5-thiadiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanol suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is reacted with an equimolar amount of2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine according to theprocedure described in Example 17, Step A, and an equimolar amount of2-[(3-hydroxy-1,2,5-thiadiazol-4-yl)methylthio]ethylamine, the titlecompound is thereby produced.

EXAMPLE 793-{2-[(2-Amino-1,2,4-thiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

Reaction of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide with oneequivalent of 2-[(2-amino-1,2,4-triazol-5-yl)methylthio]ethylamine[prepared according to general procedures described in U.S. Pat. No.3,950,353] and an excess of methylamine by the general proceduredescribed in Example 2, produces the title compound.

EXAMPLE 80

The general procedure of Example 79 is repeated except that the2-[(2-amino-1,2,4-triazol-5-yl)methylthio]ethylamine utilized therein isreplaced by an equimolar amount of

2-[(4-methyl-1,2,4-triazol-3-yl)methylthio]ethylamine,

2-[(5-methyl-1,2,3-triazol-4-yl)methylthio]ethylamine and

2-[1,2,4-triazol-3-yl)methylthio]ethylamine, respectively, [eachprepared by the general procedures described in U.S. Pat. No. 3,950,353]and there is thereby produced

3-{2-[(4-methyl-1,2,4-triazol-3-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide,

3-{2-[(5-methyl-1,2,3-triazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide and

3-methylamino-4-{2-[1,2,4-triazol-3-ylmethylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide, respectively.

EXAMPLE 813-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-{2-[(5-methyl-1,2,3-triazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is reacted with an equimolar amount of2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine according to theprocedure described in Example 17, Step A, and an equimolar amount of2-[(5-methyl-1,2,3-triazol-4-yl)methylthio]ethylamine, the titlecompound is produced.

EXAMPLE 823-{2-[(2-Dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-dimethylamino-1,2,5-thiadiazole1-oxide

When a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide [prepared inExample 4, Step A] is reacted with one equivalent of2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine [prepared inExample 33, Step E] and the resultant3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-methoxy-1,2,5-thiadiazole1-oxide is treated with an excess of dimethylamine according to theprocedure described in Example 28, the title compound is therebyproduced.

EXAMPLE 83

The general procedure of Example 82 is repeated, except that thedimethylamine utilized therein is replaced by

pyrrolidine,

piperidine,

morpholine,

thiomorpholine,

piperazine,

N-acetylpiperazine,

N-methylpiperazine,

hexamethyleneimine and

homopiperazine, respectively, and there is thereby produced

3-{2[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-(1-pyrrolidinyl)-1,2,5-thiadiazole1-oxide,

3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-(1-piperidinyl)-1,2,5-thiadiazole1-oxide,

3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-(morpholinyl)-1,2,5-thiadiazole1-oxide,

3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-(4-thiomorpholinyl)-1,2,5-thiadiazole1-oxide,

3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-(1-piperazinyl)-1,2,5-thiadiazole1-oxide,

3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-(4-acetyl-1-piperazinyl)-1,2,5-thiadiazole1-oxide,

3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-(4-methyl-1-piperazinyl)-1,2,5-thiadiazole1-oxide,

3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-(1-hexamethyleneimino)-1,2,5-thiadiazole1-oxide and

3-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-4-(1-homopiperazinyl)-1,2,5-thiadiazole1-oxide, respectively.

EXAMPLE 843-{2-[(5-Dimethylaminomethyl-2-furyl)methythio]ethylamino}-4-ethylamino-1,2,5-thiadiazole1-oxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(2.64 g; 12.3 mmoles) in 25 ml of dry methanol was added dropwise over aperiod of 30 minutes to a well stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.0 g; 12.3 mmoles) in 75 ml ofdry methanol that had been cooled to 8° in an ice-water bath. After 15minutes, 4.0 ml of ethylamine was added and the mixture stirred atambient temperature for 1 hour. The reaction mixture was evaporatedunder reduced pressure and the residue placed on 55 g of silica gel andchromatographed using a gradient elution of methylene chloride-methanol.The appropriate fractions were combined, evaporated under reducedpressure and the residue treated with ether and decanted. The residuewas treated with fresh ether to give 1.5 g of the title compound, mp68°-74°.

Anal. Calcd. for C₁₄ H₂₃ N₅ O₂ S₂ : C, 47.04; H, 6.48; N, 19.59; S,17.94. Found (corr. for 1.24% H₂ O): C, 46.54; H, 6.33; N, 19.37; S,17.96.

EXAMPLE 853-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-propylamino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(2.41 g; 11.2 mmoles) in 25 ml of dry methanol was added dropwise over aperiod of 30 minutes to a well stirred suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200ml of dry methanol that had been cooled to 2° in an ice-water bath.After 15 minutes, 4.0 ml of n-propylamine was added all at once and themixture stirred at ambient temperature for 30 minutes. The reactionmixture was evaporated under reduced pressure and the residue placed on55 g of silica gel and chromatographed using a gradient elution ofmethylene chloride-methanol. The appropriate fractions were combined,evaporated under reduced pressure and the syrup crystallized with etherto give 3.7 g of the title compound, mp 164°-166°; the NMR spectrum (100MHz) in d₆ dimethyl sulfoxide showed the presence of approximately 0.9moles of methanol.

Anal. Calcd for C₁₅ H₂₅ N₅ O₃ S₂.0.9CH₄ O: C, 45.86; H, 6.92; N, 16.82;S, 15.40. Found: C, 45.60; H, 6.93; N, 17.03; S, 15.47.

EXAMPLE 863-Amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(3.3 g; 15.4 mmoles) in 25 ml. of methanol was added dropwise over aperiod of 30 minutes to a well stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.5 g; 15.4 mmoles) in 75 ml ofmethanol that had been cooled to 8° in an ice-water bath. After 1.5hours, anhydrous ammonia was bubbled into the solution for 8 minutes andthe mixture stirred at ambient temperature for 30 minutes. The reactionmixture was evaporated under reduced pressure and the residue placed on60 g of silica gel and chromatographed using a gradient elution ofmethylene chloride-methanol. The appropriate fractions were combined andevaporated, and the product was crystallized from acetonitrile.Recrystallization from isopropyl alcohol yielded 2.59 g of the titlecompound, mp 139°-142°.

Anal. Calcd for C₁₂ H₁₉ N₅ O₂ S₂ : C, 43.75; H, 5.81; N, 21.26; S,19.46. Found: C, 43.71; H, 6.05; N, 21.32; S, 19.51.

EXAMPLE 873-Amino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(2.5 g; 11.7 mmoles) in 50 ml. of dry methanol was added dropwise over45 minutes to a well stirred suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.08 g; 11.8 mmoles) in 200ml. of dry methanol that had been cooled to 5° in an ice-water bath.After 30 minutes, anhydrous ammonia was bubbled into the solution for 10minutes and the mixture stirred at ambient temperature for 8 hours. Thereaction mixture was evaporated under reduced pressure and the residueplaced on 200 g of silica gel and chromatographed using a gradientelution of methylene chloride-methanol. The appropriate fractions werecombined and evaporated to give 3.6 g of product. Recrystallization frommethanol-ether yielded the title compound, mp 156°-158°.

Anal. Calcd for C₁₂ H₁₉ N₅ O₃ S₂ : C, 41.72; H, 5.54; N, 20.28; S,18.56. Found: C, 41.50; H, 5.52; N, 20.33; S, 18.74.

EXAMPLE 883-Amino-4-{2-[(2-guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A solution of 2-[(guanidinothiazol-4-yl)methylthio]ethylamine (from thedihydrochloride, 6.08 g; 20.0 mmoles) in 50 ml of methanol was addeddropwise, over 45 minutes, to a cold (5°) well stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (3.24 g; 20.0 mmoles) in 150 mlof methanol. After stirring at 5°-10° for 1.5 hours, anhydrous ammoniawas bubbled into the solution for 10 minutes and stirring was continuedat ambient temperature for 18 hours. The reaction mixture was evaporatedunder reduced pressure and the residue placed on 65 g of silica gel andchromatographed using a gradient elution of methylene chloride-methanol.The appropriate fractions were combined and evaporated to give 4.16 g ofproduct from methanol. Recrystallization from methanol yielded the titlecompound, mp 167°-170° (dec).

Anal. Calcd for C₉ H₁₄ N₈ OS₃ : C, 31.20; H, 4.07; N, 32.35; S, 27.76.Found (corr. for 0.48% H₂ O): C, 30.39; H, 3.97; N, 32.25; S, 27.91.

Recrystallization of the crude product from 95% ethanol yielded thetitle compound as a monohydrate, mp 136°-138° (dec).

Anal. Calcd for C₉ H₁₄ N₈ OS₃.H₂ O: C, 29.66; H, 4.42; N, 30.75; S,26.39. Found: C, 29.92; H, 4.42; N, 30.84; S, 26.58.

A sample of the product as the free base was suspended in 95% ethanol,treated with one equivalent of aqueous 6.0 N hydrochloric acid andfiltered to yield the hydrochloride salt, mp 200°-201° C. (dec.)

Anal. Calcd for C₉ H₁₅ ClN₈ OS₃ : S, 28.23; H, 3.95; N, 29.26; Cl, 9.26Found (corr. for 1.02% H₂ O): C, 28.26; H, 3.83; N, 29.41; Cl, 9.53

EXAMPLE 893-Benzylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(2.4 g; 11.2 mmoles) in 30 ml of dry methanol was added dropwise over aperiod of 35 minutes to a stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200ml of dry methanol that had been cooled to 1°-3° in an ice water bath.After 15 minutes at 1°-3°, benzylamine (1.8 g, 1.83 ml; 16.8 mmoles) wasadded and the solution stirred at ambient temperature for 1 hour. Thereaction mixture was evaporated under reduced pressure and the residueplaced on 50 g of silica gel and chromatographed using a gradientelution of methylene chloride-methanol. The appropriate fractions werecombined to give 4.1 g of product. Recrystallization from aqueousmethanol and then methanol yielded the title compound, mp 152° (dec);the NMR spectrum (100 MHz) in d₆ dimethyl sulfoxide showed the presenceof approximately 1.0 mole of methanol.

Anal. Calcd for C₁₉ H₂₅ N₅ O₃ S₂.CH₄ O: C, 51.37; H, 6.25; N, 14.98.Found: C, 51.51; H, 6.05; N, 14.78.

EXAMPLE 903-{2-[(3-{Dimethylaminomethyl}phenyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole,1,1-dioxide

A solution of 2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamine(2.51 g; 11.2 mmoles) [prepared according to the procedure described inBelgian Pat. No. 867,106] in 25 ml of dry methanol was added dropwiseover 30 minutes to a well stirred suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.0 g; 11.2 mmoles) in 200ml of dry methanol that had been cooled to 2° in an ice-water bath.After 15 minutes at 2°-5°, anhydrous methylamine was bubbled into thesolution for 10 minutes and the solution was then stirred at ambienttemperature for 30 minutes. The reaction mixture was evaporated underreduced pressure and the residue placed on 60 g of silica gel andchromatographed using a gradient elution of methylene chloride-methanol.The appropriate fractions were combined to give 2.96 g of product.Recrystallization from acetonitrile and then from methanol yielded andtitle compound, mp 152°-158°; the NMR spectrum (100 mHz) in d₆ dimethylsulfoxide showed the presence of approximately 0.6 mole of methanol.

Anal. Calcd for C₁₅ H₂₃ N₅ O₂ S₂.0.6CH₄ O: C, 48.20; H, 6.59; N, 18.02;S, 16.49. Found: C, 47.99; H, 6.78; N, 17.81; S, 16.09.

EXAMPLE 913-Amino-4-{2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A solution of 2-[(3-{dimethylaminomethyl}phenyl)methylthio]ethylamine(2.77 g; 12.3 mmoles) in 25 ml of dry methanol was added dropwise over45 minutes to a well stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole1-oxide (2.0 g; 12.3 mmoles) in 100 ml of dry methanol that had beencooled to 5° in an ice-water bath. When the addition was completed, thesolution was stirred at ambient temperature for 1.5 hours and thencooled to 5° and anhydrous ammonia was bubbled into the solution for 8minutes. After stirring 16 hours at ambient temperature, the reactionmixture was evaporated under reduced pressure and the residue placed on55 g of silica gel and chromatographed using a gradient elution ofmethylene chloride-methanol. The appropriate fractions were combined togive 3.0 g of product from acetonitrile. Recrystallization from acetoneyielded the title compound, mp 122°-125°.

Anal. Calcd for C₁₄ H₂₁ N₅ OS₂ : C, 49.53; H, 6.23; N, 20.63; S, 18.89.Found: C, 49.18; H, 6.08; N, 20.93; S, 19.25.

EXAMPLE 923-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

A solution of 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine(1.5 g; 6.5 mmoles) in 25 ml of dry methanol was added dropwise over aperiod of 45 minutes to a stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.06 g; 6.5 mmoles) in 150 mlof dry methanol that had been cooled to 3° in an ice-water bath. After15 minutes at 3°, anhydrous methylamine was bubbled into the solutionfor 5 minutes and the solution was stirred for 15 minutes. The reactionmixture, after standing overnight at ambient temperature, was evaporatedunder reduced pressure and the residue placed on 75 g of silica gel andchromatographed using a gradient elution of acetonitrile-methanol. Theappropriate fractions were combined to give crystalline product fromacetonitrile. Recrystallization from acetonitrile yielded the titlecompound, mp 98.5°-102°.

Anal. Calcd for C₁₃ H₂₁ N₅ OS₃ : C, 43.42; H, 5.89; N, 19.48; S, 26.76.Found: C, 43.70; H, 5.58; N, 19.71; S, 26.79.

EXAMPLE 933-Amino-4-{4-(5-dimethylaminomethyl-2-furyl)butylamino}-1,2,5-thiadiazole1,1-dioxide

A solution of 4-(5-dimethylaminomethyl-2-furyl)butylamine (1.61 g; 8.2mmoles) in 25 ml of dry methanol was added dropwise over a period of 35minutes to a well stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (1.46 g; 8.2 mmoles) in 150 ml of dry methanol that had beencooled to 0°-3° in an ice-water bath. After 15 minutes, anhydrousammonia was bubbled into the solution for 5 minutes and the solution wasstirred for 30 minutes. The reaction mixture was evaporated underreduced pressure and the residue placed on 60 g of silica gel andchromatographed using a gradient elution of acetonitrile-methanol. Theappropriate fractions were combined and evaporated to give 1.68 g ofproduct. Crystallization from acetonitrile yielded the title compound,mp 154°-156° (dec).

Anal. Calcd for C₁₃ H₂₁ N₅ O₃ S: C, 47.69; H, 6.47; N, 21.39; S, 9.80.Found: C, 47.73; H, 6.28; N, 21.43; S, 9.84.

EXAMPLE 943-Amino-4-{2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

A solution of2-[(2-dimethylaminomethyl-4-thiazolyl)methylthio]ethylamine (0.9 g; 3.89mmoles) in 20 ml of dry methanol was added dropwise over 40 minutes to awell stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide(0.69 g; 3.89 mmoles) in 70 ml of methanol that had been cooled to 8°,anhydrous ammonia was bubbled into the solution for 8 minutes and thenthe solution was allowed to stir at ambient temperature for 18 hours.The reaction mixture was evaporated under reduced pressure and theresidue placed on 150 g of silica gel and chromatographed using agradient elution of acetonitrile-methanol. The appropriate fractionswere combined and evaporated to give 0.66 g of the product. The foam wasdissolved in 2-propanol and evaporated to dryness to give the titlecompound, mp 60°-65°; the NMR spectrum (100 MHz) in d₆ dimethylsulfoxide showed the presence of approximately 0.15 mole of 2-propanol.

Anal. Calcd for C₁₁ H₁₈ N₆ S₃ O₂.0.15C₃ H₈ O: C, 37.02; H, 5.21; N,22.62; S, 25.89. Found (corr. for 2.79% H₂ O): C, 36.75; H, 5.13; N,21.75; S, 25.03.

EXAMPLE 953-{2-[(2-Guanidinothiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

(A) Ethyl 2-Guanidino-5-thiazolecarboxylate Hydrochloride

A solution of amidinothiourea (117 g; 0.99 mole) and ethylchloro-α-formylacetate (150 g; 1.0 mole) in 3.5 liters of absoluteethanol was stirred at ambient temperature for 18 hours and then heatedat reflux temperature for 1 hour. At this time additional ethylchloro-α-formylacetate (20.0 g; 0.13 mole) was added and 1 hour lateranother 20.0 g of ethyl chloro-α-formylacetate was added. After 2 hoursof additional heating at reflux temperature, the reaction mixture wasevaporated under reduced pressure and the residue triturated with 1.5liters of acetone and filtered to give 103 g of product.Recrystallization from 2-propanol yielded the title compound, mp204°-206°.

Anal. Calcd for C₇ H₁₁ ClN₄ O₂ S: C, 33.53; H, 4.43; N, 22.35; Cl,14.14; S, 12.79. Found: C, 33.38; H, 4.40; N, 22.54; Cl, 13.97; S,12.92.

(B) 2-Guanidino-5-hydroxymethylthiazole

Ethyl 2-guanidino-5-thiazolecarboxylate hydrochloride (1.0 g; 3.99mmoles) [prepared in Step A] was added to a cooled (ice-water bath)suspension of lithium aluminum hydride (0.46 g; 12.1 mmoles) in 25 ml oftetrahydrofuran. The reaction mixture was then heated at refluxtemperature for 2 hours, cooled, decomposed with 0.46 ml H₂ O, 0.46 mlof 15% NaOH and 1.38 ml H₂ O and filtered. The filtrate was dried andevaporated under reduced pressure to give 0.61 g of product.Recrystallization from acetonitrile yielded the title compound, mp168°-170°.

Anal. Calcd for C₅ H₈ N₄ OS: C, 34.87; H, 4.68; N, 32.54; S, 18.62.Found: C, 34.55; H, 4.52; N, 32.63; S, 18.54.

(C) 2-[(2-Guanidinothiazol-5-yl)methylthio]ethylamine

Cysteamine hydrochloride (10.6 g; 9.3 mmoles) and2-guanidino-5-hydroxymethylthiazole (16.0 g; 9.3 mmoles) [prepared inStep B] were dissolved in 80 ml of concentrated hydrochloric acid andthe solution stirred at ambient temperature for 1 hour and then heatedat reflux temperature for 3 hours. The reaction mixture was cooled, madebasic (pH 11) with 40% aqueous NaOH and filtered to give 15 g ofproduct. Recrystallization from acetonitrile yielded the title compound,mp 150°-153°.

Anal. Calcd for C₇ H₁₃ N₅ S₂ : C, 36.34; H, 5.66; N, 30.27; S, 27.72.Found: C, 36.29; H, 5.70; N, 30.40; S, 27.64.

(D)3-{2-[(2-Guanidinothiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(2-guanidinothiazol-5-yl)methylthio]ethylamine (2.0 g;8.64 mmoles) [prepared in Step C] in 60 ml of methanol was addeddropwise over 40 minutes to a well stirred suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1.54 g; 8.64 mmoles) in 160ml of methanol that had been cooled to 8° in an ice-water bath. Whilemaintaining the temperature at 8°, anhydrous methylamine was bubbledinto the solution for 8 minutes. After stirring at ambient temperaturefor 18 hours, the reaction mixture was evaporated under reduced pressureand the residue placed on 175 g of silica gel and chromatographed usinga gradient elution of acetonitrile-methanol. The appropriate fractionswere combined to give 1.3 g of product. Recrystallization from methanolyielded the title compound, mp 225°-226° (dec.).

Anal. Calcd for C₁₀ H₁₆ N₈ O₂ S₃ : C, 31.90; H, 4.28; N, 29.76; S,25.55. Found: C, 32.07; H, 4.14; N, 29.91; S, 25.60.

EXAMPLE 963-Amino-4-{2-[(2-guanidinothiazol-5-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A solution of 2-[(2-guanidinothiazol-5-yl)methylthio]ethylamine (3.0 g;13.0 mmoles) [prepared in Example 95, Step C] in 70 ml of methanol wasadded dropwise over 40 minutes to a well stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.1 g; 13.0 mmoles) in 200 mlof methanol that had been cooled to 8°, and anhydrous ammonia was thenbubbled into the solution for 8 minutes. After stirring at ambienttemperature for 18 hours, the reaction mixture was evaporated underreduced pressure and the residue placed on 225 g of silica gel andchromatographed using a gradient elution of acetonitrile-methanol. Theappropriate fractions were combined to give 3.6 g of the title compound,mp 85°-132°; the NMR spectrum (100 MHz) in d₆ dimethyl sulfoxide showedthe presence of approximately 0.3 mole of acetonitrile.

Anal. Calcd for C₉ H₁₄ N₈ OS₃.0.3C₂ H₃ N: C, 32.24; H, 4.22; N, 32.41;S, 26.71. Found (corr. for 1.84% H₂ O): C, 32.63; H, 4.33; N, 32.55; S,26.62.

EXAMPLE 973-Cyclopropylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 13 was repeated, except that the2-propynylamine utilized therein was replaced by an equimolar amount ofcyclopropylamine, and the product was crystallized from methanol.Recrystallization from isopropyl alcohol yielded 3.5 g of the titlecompound, mp 194°-195° (dec.); the NMR spectrum (100 MHz) in d₆ dimethylsulfoxide and showed the presence of approximately 1.0 mole of isopropylalcohol.

Anal. Calcd for C₁₅ H₂₃ N₅ O₃ S₂.C₃ H₈ O: C, 48.52; H, 7.01; N, 15.72.Found: C, 48.36; H, 6.95; N, 14.87.

EXAMPLE 983-Cyclopropylmethylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 13 was repeated, except that the2-propynylamine utilized therein was replaced by an equimolar amount ofcyclopropylmethyamine, and the product was crystallized from methanol.Recrystallization from methanol yielded 1.6 g of the title compound, mp86°-89° (dec.); the NMR spectrum (100 MHz) in d₆ dimethyl sulfoxideshowed the presence of approximately 1.25 moles of methanol.

Anal. Calcd for C₁₆ H₂₅ N₅ O₃ S₂.1.25 CH₄ O: C, 47.13, H, 6.88; N,15.93. Found (corr. for 0.68% H₂ O): C, 47.40; H, 6.49; N, 15.77.

EXAMPLE 993-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-morpholino-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 28 was repeated, except that thedimethylamine utilized therein was replaced by an equimolar amount ofmorpholine. After column chromatography, the product was crystallizedfrom isopropyl alcohol. The mixture was diluted with Skellysolve B andfiltered to yield the title compound, mp 122°-127°.

Anal. Calcd for C₁₆ H₂₅ N₅ O₄ S₂ : C, 46.24; H, 6.06; N, 16.86. Found(corr. for 0.61% H₂ O): C, 45.82; H, 6.06; N, 16.62.

EXAMPLE 1003-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-(2-methylethylamino)-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 13 was repeated, except that the2-propynylamine utilized therein was replaced by an equimolar amount of2-methoxyethylamine. After column chromatography, the residue wastreated with isopropyl alcohol, evaporated to near dryness and cooled togive 3.79 g of product. Recrystallization from isopropyl alcohol yieldedthe title compound, mp 56°-58°; the NMR spectrum (100 MHz) in d₆dimethyl sulfoxide showed the presence of approximately 0.6 moles ofisopropyl alcohol.

Anal. Calcd for C₁₅ H₂₅ N₅ O₄ S₂.0.6 C₃ H₈ O: C, 45.90; H, 6.83; N,15.93. Found (corr. for 0.74% H₂ O): C, 45.50; H, 6.72; N, 15.63.

EXAMPLE 1013-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-pyrrolidino-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 28 was repeated, except that thedimethylamine utilized therein was replaced by an equimolar amount ofpyrrolidone. The crude reaction mixture was evaporated under reducedpressure, treated with isopropyl alcohol and filtered to yield 3.9 g ofthe title compound, mp 151°-152°.

Anal. Calcd for C₁₆ H₂₅ N₅ O₃ S₂ : C, 48.09; H, 6.31; N, 17.53. Found:C, 48.00; H, 6.10; N, 17.71.

EXAMPLE 1023-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]-ethylamino}-4-piperidino-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 28 was repeated, except that thedimethylamine utilized therein was replaced by an equimolar amount ofpiperidine. Chromatography yielded 3.8 g of product. Recrystallizationfrom hot aqueous ethanol yielded the title compound, mp 160°-108°.

Anal. Calcd. for C₁₈ H₂₇ N₅ O₃ S₂ : C, 49.37; H, 6.58; N, 16.94. Found(corr. for 0.2% H₂ O): C, 49.17; H, 6.52; N, 17.14.

EXAMPLE 1033-Butylamino-4-{2-[(5-dimethylaminomethyl-2-furyl)methylthio]-ethylamino}-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 13 was repeated, except that the2-propynylamine utilized therein was replaced by an equimolar amount ofbutylamine. The crude product was chromatographed three times and driedwith heating under high vacuum for 3.5 hours to yield 1.81 g of thetitle compound as a somewhat gummy foam.

Anal. Calcd for C₁₆ H₂₇ N₅ O₃ S₂ : C, 47.86; H, 6.78; N, 17.44. Found(corr. for 1.34% H₂ O): C, 47.60; H, 6.81; N, 17.81.

EXAMPLE 1043-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-[(2-pyridyl)methylamino]-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 13 was repeated, except that the2-propynylamine utilized therein was replaced by an equimolar amount of2-aminomethylpyridine. The appropriate fractions from columnchromatography were combined to give 3.9 g of product. Tworecrystallizations from isopropyl alcohol yielded the title compound, mp43°-45°. A sample was recrystallized from absolute ethanol and the solidwas heated under vacuum at 60° for 6 hours to give a melt. The melt wasdissolved in hot isopropyl alcohol, collected by filtration at ambienttemperature and dried under high vacuum to yield the title compound, mp45°-47°; the NMR spectrum (100 MHz) in d₆ dimethyl sulfoxide showed thepresence of approximately 1.25 moles of isopropyl alcohol.

Anal. Calcd for C₁₈ H₂₄ N₆ O₃ S₂.1.25 C₃ H₈ O: C, 51.05; H, 6.70; N,16.42. Found (corr. for 0.58% H₂ O): C, 51.08; H, 6.32; N, 16.03.

EXAMPLE 1053-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-hydroxylamino-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 13 was repeated, except that the2-propynylamine utilized therein was replaced by an equimolar amount ofhydroxylamine. The crude reaction mixture which had deposited theproduct as an oil was heated to reflux temperature until all the productcrystallized, then filtered and dried to give 2.59 g of the titlecompound, mp 203°-205°.

Anal. Calcd for C₁₂ H₁₉ N₅ O₄ S₂ : C, 39.87; H, 5.30; N, 19.38; S,17.74. Found (corr. for 1.18% H₂ O): C, 39.53; H, 5.04; N, 19.61; S,17.62.

EXAMPLE 1063-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-dodecylamino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-furyl)methylthio]ethylamine(2.41 g; 11.2 mmoles) in 25 ml of methanol was added dropwise to a wellstirred cold suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide(2.0 g; 11.2 mmoles) in 200 ml of methanol. After stirring at 2°-5° for15 minutes, a solution of dodecylamine (4.15 g; 22.4 mmoles) in 25 ml ofmethanol was added all at once, and stirring was continued at ambienttemperature for 18 hours. The reaction mixture was filtered andevaporated under reduced pressure, and the residue placed on 60 g ofsilica gel and chromatographed using a gradient elution of methylenechloride-methanol. The appropriate fractions were combined, evaporatedand the residue was rechromatographed on 60 g of silica gel using agradient elution of acetonitrile-methanol. The appropriate fractionsfrom the second chromatography were combined, concentrated under reducedpressure and the crystallized product was collected by filtration anddried to give 2.13 g of the title compound, mp 136°-139°.

Anal. Calcd for C₂₄ H₄₅ N₅ O₃ S₂ : C, 55.89; H, 8.79; N, 13.58; S,12.43. Found: C, 56.16; H, 8.57; N, 13.38; S, 12.61.

EXAMPLE 1073-{2-[(5-Dimethylaminomethyl-2-furyl)methylthio]ethylamino}-4-methoxyamino-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 13 was repeated, except that the2-propynylamine utilized therein was replaced by an equimolar amount ofmethoxyamine. The reaction mixture was stirred at ambient temperatureovernight, during which a crystalline precipitate formed. The solutionwas cooled and filtered, and the recovered solid was dried to yield 3.8g of the title compound, mp 224°-226° (dec.).

Anal. Calcd for C₁₃ H₂₁ N₅ O₄ S₂ : C, 41.59; H, 5.64; N, 18.65; S,17.08. Found (corr. for 0.79% H₂ O): C, 41.25; H, 5.54; N, 18.50; S,17.16.

EXAMPLE 1083-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-propylamino-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 65 was repeated, except that themethylamine utilized therein was replaced by an equimolar amount ofpropylamine. Chromatography gave 3.5 g of crystalline product.Recrystallization from acetonitrile yielded the title compound, mp194°-196° (dec.).

Anal. Calcd for C₁₅ H₂₅ N₅ O₂ S₃ : C, 44.64; H, 6.24; N, 17.35; S,23.84. Found: C, 44.66; H, 6.02; N, 17.88; S, 23.87.

EXAMPLE 1093-Amino-4-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]-ethylamino}-1,2,5-thiadiazole1-oxide

A solution of 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine(2.84 g; 12.3 mmoles) in 25 ml of methanol was added dropwise over aperiod of 35 minutes to a stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.0 g; 12.3 mmoles) in 200 mlof methanol that had been cooled to 3° in an ice-water bath. Afterstirring for 15 minutes, anhydrous ammonia was bubbled into the solutionfor 5 minutes. The reaction mixture was evaporated under reducedpressure, and the residue placed on 60 g of silica gel andchromatographed using a gradient elution of methylene chloride-methanol.The appropriate fractions were combined to give 1.73 g of product.Recrystallization from acetonitrile yielded the title compound, mp149°-152° (dec.).

EXAMPLE 1103-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-[(3-pyridyl)methylamino]-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 65 was repeated, except that themethylamine utilized therein was replaced by an equimolar amount of3-aminomethylpyridine. The appropriate fractions from columnchromatography gave 3.10 g of the title compound as an oil. The productwas dissolved in excess 5% HCl, evaporated and then triturated withisopropyl alcohol to give a solid product. Recrystallization from 95%aqueous ethanol yielded the title compound as a dihydrochloride salt, mp143°-146.5°.

Anal. Calcd for C₁₈ H₂₆ Cl₂ N₆ O₂ S₃ : C, 41.13; H, 4.99; N, 15.99; S,18.30. Found (corr. for 2.04% H₂ O): C, 41.25; H, 4.90, N, 16.18; S,18.52.

EXAMPLE 1113-Amino-4-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine(2.0 g; 8.68 mmoles) in 25 ml of methanol was added dropwise over aperiod of 35 minutes to a stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1.55 g; 8.68 mmoles) in 200ml of methanol that had been cooled to 3° in an ice-water bath. Afterstirring for 15 minutes, anhydrous ammonia was bubbled through thesolution for 10 minutes. The reaction mixture was evaporated underreduced pressure to give 3.3 g of the title compound.

The NMR spectrum (100 MHz) in d₆ dimethyl sulfoxide gave the followingresonances δ: 6.88 (d, 1H); 6.78 (d, 1H); 4.03 (s, 2H); 3.61 (s, 2H);3.54 (t, 2H); 2.74 (t, 2H); 2.22 (s, 6H); it also showed the presence ofapproximately 2/3 mole of methanol.

EXAMPLE 1123-Benzylamino-4-{2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 65 was repeated, except that themethylamine utilized therein was replaced by an equimolar amount ofbenzylamine. The reaction mixture was evaporated under reduced pressureto give product. Recrystallization from methanol with charcoal treatmentyielded 2.63 g of the title compound, mp 203°-205.5° (dec.).

Anal. Calcd for C₁₉ H₂₅ N₅ O₂ S₃ : C, 50.53; H, 5.58; N, 15.51; S,21.30. Found: C, 50.79; H, 5.34; N, 15.78; S, 20.94.

EXAMPLE 1133-[3-(3-Dimethylaminomethylphenoxy)propylamino]-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A solution of 3-[3-(dimethylaminomethyl)phenoxy]propylamine (2.73 g;14.0 mmoles) [prepared according to the procedure described in BelgianPatent 867,106] in 50 ml of methanol was added dropwise over a period of60 minutes to a stirred suspension of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide (2.5 g; 14.0 mmoles) in 250 ml of methanol that had beencooled to 4° in an ice-water bath. After stirring for 20 minutes,anhydrous methylamine was bubbled into the solution for 10 minutes. Thereaction mixture was evaporated under reduced pressure and the residueplaced on 75 g of silica gel and chromatographed using a gradientelution of methylene chloride-methanol. The appropriate fractions werecombined and evaporated, and then dissolved in n-propanol and treatedwith one equivalent of HCl to give the product as a hydrochloride salt.Recrystallization from aqueous ethanol yielded the title compound as ahydrochloride salt, mp 140°-145°.

Anal. Calcd for C₁₅ H₂₄ ClN₅ O₃ S: C, 46.20; H, 6.20; N, 17.96; S, 8.22;Cl, 9.09. Found (corr. for 3.79% H₂ O): C, 46.21; H, 6.06, N, 18.24; S,8.38; Cl, 9.05.

EXAMPLE 1143-{2-[(2-Dimethylaminomethylthiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A. 5-Carbethoxy-2-(N-carbophenoxy-N-methylamino)methylthiazole

(N-Carbophenoxy-N-methylamino)thioacetamide (46.7 g; 0.21 moles) wascombined with ethyl α-formylchloroacetate (30.0 g; 0.20 moles) in 270 mlof 1,2-dichloroethane and heated to reflux temperature for 2 hours. Anadditional amount of ethyl α-formylchloroacetate (3.0 g; 0.02 moles) wasadded and heating was continued for 1.5 hours. The reaction mixture wasextracted with two 300 ml portions of cold 5% aqueous sodium carbonate,then washed with two 300 ml portions of water and dried over Na₂ SO₄.Evaporation gave the product as an oil which slowly crystallized.Recrystallization from 2-propanol yielded 26 g of the title compound, mp81°-83°.

Anal. Calcd for C₁₅ H₁₆ N₂ O₄ S: C, 56.24; H, 5.03; N, 8.74; S, 10.01.Found: C, 56.48; H, 4.97; N, 8.54; S, 10.17.

B. 2-Hydroxymethyl-5-dimethylaminomethylthiazole

5-Carbethoxy-2-(N-carbophenoxy-N-methylamino)methylthiazole (19.8 g;0.62 moles) [prepared in Step A] was added to a cold (5°) stirredsuspension of lithium aluminum hydride (6.12 g; 0.16 moles) in 544 ml ofdry tetrahydrofuran. The reaction mixture was heated to refluxtemperature for 0.5 hour and then cooled to ambient temperature anddecomposed, filtered through celite and evaporated under reducedpressure. The residue was dissolved in 80 ml of 3 N HCl and extractedwith ether. The aqueous phase was adjusted to pH 8 and extracted withmethylene chloride. The organic phase was dried, filtered and evaporatedunder vacuum to give 6.0 g of the title compound as an oil. The NMRspectrum (60 MHz) in CDCl₃ gave the following resonances δ: 7.50 (s,1H); 4.85 (s, 2H); 4.15 (s, 1H); 3.75 (s, 2H); 2.35 (s, 6H).

C. 2-Chloromethyl-5-dimethylaminomethylthiazole hydrochloride

Thionyl chloride (27.4 g; 0.16 moles) was added dropwise to a cooled(ice-water bath) solution of5-hydroxymethyl-2-dimethylaminomethylthiazole (8.9 g; 52.0 mmoles)[prepared in Step B] in 300 ml of methylene chloride. The mixture washeated at reflux temperature for 2 hours and then cooled and evaporatedunder reduced pressure to give 12.3 g of product. Crystallization fromacetonitrile yielded the title compound, mp 143°-144°.

Anal. Calcd for C₇ H₁₂ Cl₂ N₂ S: C, 37.01; H, 5.32; N, 12.33; Cl, 31.63.Found (corr. for 0.91% H₂ O): C, 36.88; H, 5.11; N, 12.14; Cl, 31.65.

D. 2-[(2-Dimethylaminomethylthiazol-5-yl)methylthio]ethylamine

Cysteamine hydrochloride (0.2 g; 1.76 mmoles) and5-chloromethyl-2-dimethylaminomethylthiazole hydrochloride (0.4 g; 1.76mmoles) [prepared in Step C] were dissolved in 2.5 ml of concentratedhydrochloric acid and the solution was heated at an oil bath temperatureof 100°. After 2 hours, the mixture was evaporated under reducedpressure and the residue made basic with 40% aqueous sodium hydroxidesolution. The aqueous phase was extracted with methyl acetate and theorganic phase was dried, filtered and evaporated to give 0.3 g of thetitle compound as an oil. The NMR spectrum (60 MHz) in CDCl₃ gave thefollowing resonances δ: 7.50 (s, 1H), 3.95 (s, 2H); 3.76 (s, 2H); 2.85(m, 4H); 2.40 (s, 6H), 1.85 (s, 2H).

E.3-{2-[(2-Dimethylaminomethylthiazol-5-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A solution of2-[(2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamine (1.55 g; 6.7mmoles) [prepared in Step D] in 60 ml of methanol was added dropwiseover 40 minutes to a partial suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1.19 g; 6.7 mmoles) in 130ml of methanol that had been cooled to 8°. Upon completion of theaddition, anhydrous methylamine was bubbled into the solution for 8minutes, then stirred at ambient temperature overnight. The reactionmixture was evaporated under reduced pressure and the residuechromatographed on 150 g of silica gel using a gradient elution ofacetonitrilemethanol. The appropriate fractions were combined to give1.05 g of product. Recrystallization from 2-propanol yielded the titlecompound, mp 170°-172°.

Anal. Calcd for C₁₂ H₂₀ N₆ O₂ S₃ : C, 38.28; H, 5.36; N, 22.33; S,25.56. Found: C, 38.31; H, 5.32; N, 22.13; S, 25.96.

EXAMPLE 1153-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1-oxide

The general procedure of Example 31 is repeated except that the3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide utilized therein wasreplaced by an equimolar amount of the corresponding 1-oxide. Theappropriate fractions from column chromatography were combined to give4.5 g of product. Crystallization from absolute ethanol yielded 3.05 gof the title compound, mp 175°-177°.

Anal. Calcd for C₁₀ H₁₆ N₈ OS₃ : C, 33.32; H, 4.47; N, 31.09; S, 26.68.Found: C, 33.10; H, 4.42; N, 31.00; S, 26.51.

EXAMPLE 1163-{2-[(2-Guanidinothiazol-4-yl)methylthio]ethylamino}-4-hydroxy-1,2,5-thiadiazole1-oxide

A solution of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine (4.15 g;17.9 mmoles) in 50 ml of methanol was added dropwise over a 30 minuteperiod to a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.91 g;17.9 mmoles) in 350 ml of methanol that had been cooled in an ice-waterbath. The reaction mixture was treated with a solution of sodiumhydroxide pellets (3.58 g; 89.5 mmoles) in methanol. After stirringovernight at ambient temperature, the mixture was neutralized with 14.9ml (89.5 mmoles) of aqueous 6.0 N HCl and after 10 minutes wasevaporated under reduced pressure. The solid residue was triturated for2 hours with 70 ml of water at ambient temperature and filtered to giveproduct. Recrystallization from water yielded the title compound, mp148°-151°.

Anal. Calcd for C₉ H₁₃ N₇ O₂ S₃ : C, 31.11; H, 3.77; N, 28.22; S, 27.69.Found (corr. for 5.52% H₂ O): C, 30.95; H, 3.76; N, 28.27; S, 28.11.

EXAMPLE 1173-Amino-4-{2-[(2-{2-methylguanidino}thiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A. 2-{[2-(2-Methylguanidino)thiazol-4-yl]methylthio}ethylamine

Cysteamine hydrochloride (1.89 g; 16.6 mmoles) and2-(2-methylguanidino)-4-chloromethylthiazole hydrochloride (4.0 g; 16.6mmoles) [prepared from (N-methylamidino)thiourea and1,3-dichloro-2-propanone] were combined in 20 ml of concentratedhydrochloric acid and the solution was heated at an oil bath temperatureof 100°. After 2 hours the mixture was evaporated under reduced pressureand the residue made basic with 40% aqueous NaOH solution. The aqueousphase was extracted several times with methyl acetate and the organicphase was dried, filtered and evaporated to give 3.35 g of the titlecompound. The NMR spectrum (60 MHz) in D₂ O gave the followingcharacteristic resonances δ: 6.52 (s, 1H), 3.60 (s, 2H), 2.70 (m, 7H).

B.3-Amino-4-{2-[(2-{2-methylguanidino}thiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A solution of2-[(2-{2-methylguanidino}thiazol-4-yl)methylthio]ethylamine (2.1 g; 8.56mmoles) [prepared in Step A] in 50 ml of methanol was added dropwiseover 30 minutes to a solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide(1.39 g; 8.56 mmoles) in 170 ml of methanol that had been cooled to 7°.Anhydrous ammonia was bubbled into the solution for 7 minutes, thenstirred at ambient temperature overnight. The reaction mixture wasevaporated under reduced pressure and the residue chromatographed on 100g of silica gel (230-400 mesh) by flash chromatography using a gradientelution of acetonitrile-methanol. The appropriate fractions werecombined, evaporated and the residue chromatographed on a PreparativeHPLC system using μ-porasil silica gel. The appropriate fractions werecombined, concentrated to a small volume and filtered to yield the titlecompound, mp 86°-91°; the NMR spectrum (100 MHz) in d₆ dimethylsulfoxide showed the presence of approximately 0.8 moles of ethanol.

Anal. Calcd for C₁₀ H₁₆ N₈ OS₃ ·0.8 C₂ H₆ O: C, 35.06; H, 5.28; N,28.20; S, 24.21. Found (corr. for 1.64% H₂ O): C, 35.66; H, 5.05; N,28.33; S, 23.96.

EXAMPLE 1183-Amino-4-[3-(3-dimethylaminomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide

A solution of 3-[3-(dimethylaminomethyl)phenoxy]propylamine (2.5 g; 12.9mmoles) in 35 ml of methanol was added dropwise over a period of 30minutes to a stirred solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxidein 200 ml of methanol that had been cooled to 2° in an ice-water bath.After stirring for 15 minutes, anhydrous ammonia was bubbled into thesolution for 5 minutes. The reaction mixture was evaporated underreduced pressure to give crystalline product. Two recrystallizationsfrom methanol yielded the title compound, mp 165.5°-166.5° (dec.).

Anal. Calcd for C₁₄ H₂₁ N₅ O₂ S: C, 51.99; H, 6.55; N, 21.66; S, 9.92.Found: C, 51.58; H, 6.49; N, 22.03; S, 10.19.

EXAMPLE 1193-Amino-4-{2-[(2-methylaminothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A. 2-[(2-Methylaminothiazol-4-yl)methylthio]ethylamine

Cysteamine hydrochloride (2.8 g; 24.6 mmoles) and2-methylamino-4-chloromethylthiazole (4.0 g; 24.6 mmoles) [prepared fromN-methylthiourea and 1,3-dichloro-2-propane] were dissolved in 20 ml ofconcentrated hydrochloric acid and the solution was heated at an oilbath temperature of 100°. After 30 hours of heating, the reactionmixture was evaporated under reduced pressure and the residue made basicwith 40% aqueous NaOH solution. The aqueous phase was extracted withmethyl acetate, dried, filtered and evaporated to give 1.75 g of thetitle compound as an oil which was used without further purification inStep B.

B.3-Amino-4-{2-[(2-methylaminothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

The product of Step A, above, was reacted sequentially with3,4-dimethoxy-1,2,5-thiadiazole 1-oxide and anhydrous ammonia accordingto the general procedure of Example 117, Step B, and chromatographed asdescribed therein. The appropriate fractions from flash chromatographywere combined and evaporated to give 0.5 g of product as a foam.Crystallization from acetone yielded the title compound, mp 180°-183°(dec.).

Anal. Calcd for C₉ H₁₄ N₆ OS₃ : C, 33.94; H, 4.43; N, 26.39; S, 30.21.Found (corr. for 1.41% H₂ O): C, 33.96; H, 4.11; N, 26.27; S, 30.44.

EXAMPLE 1203-Amino-4-{2-[(2-{2,3-dimethylguanidino}thiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A. 2-[(2-{2,3-Dimethylguanidino}thiazol-4-yl)methylthio]ethylaminedihydrochloride

Cysteamine hydrochloride (2.25 g; 19.6 mmoles) and4-chloromethyl-2-(2,3-dimethylguanidino)thiazole (5 g; 19.6 mmoles)[prepared from 1,3-dichloro-2-propanone and(N,N'-dimethylamidino)thiourea which is itself prepared from dimethylcyanodithioiminocarbonate and methylamine] were dissolved in 17.5 ml ofconcentrated hydrochloric acid and heated at an oil bath temperature of100°. After 24 hours the reaction mixture was evaporated under reducedpressure and the residue crystallized from absolute ethanol to yield thetitle compound, mp 243°-245°.

B.3-Amino-4-{2-[(2-{2,3-dimethylguanidino}thiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

The product of Step A, above, was sequentially reacted with3,4-dimethoxy-1,2,5-thiadiazole 1-oxide and anhydrous ammonia by thegeneral procedure of Example 117, Step B. The crude reaction mixture wasevaporated under reduced pressure and the residue crystallized frommethanol to give the title compound, mp 201°-203° (dec.).

Anal. Calcd for C₁₁ H₁₈ N₈ OS₃ : C, 35.28; H, 4.84; N, 29.92; S, 25.69.Found (corr. for 0.88% H₂ O): C, 34.93; H, 4.56; N, 30.27; S, 25.92.

EXAMPLE 1213,4-Bis-{2-[(2guanidinothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

To a solution of sodium methoxide (2.16 g; 40.0 mmoles) in 100 ml of CH₃OH that was cooled to 0° in an ice-water bath was added2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine dihydrochloride (6.09g; 20.0 mmoles) and, after 20 minutes of stirring, the solution wastreated with 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.62 g; 10mmoles). The reaction mixture was stirred at ambient temperature for 65hours and evaporated under reduced pressure. The residue waschromatographed on 100 g of silica gel (230-400 mesh) by flashchromatography using a gradient elution of acetonitrile-methanol. Theappropriate fractions were combined, evaporated and the residuechromatographed on a Preparative HPLC system using μ-porasil silica gel.The appropriate fractions were combined, and evaporated under reducedpressure to give the title compound as an amorphous solid; the NMRspectrum (100 MHz) in d₆ dimethyl sulfoxide showed the presence ofapproximately 0.11 mole of ethanol.

Anal. Calcd for C₁₆ H₂₄ N₁₂ OS₅.0.11C₂ H₆ O: C, 34.42; H, 4.39; N,29.71; S, 28.33. Found (corr. for 1.86% H₂ O): C, 34.95; H, 4.41; N,29.04; S, 27.71.

EXAMPLE 1223-{2-[(2-Aminothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A. 2-[(2-Aminothiazol-4-yl)methylthio]ethylamine dihydrochloride

Cysteamine hydrochloride (5.65 g; 50.0 mmoles) and2-amino-4-chloromethylthiazole hydrochloride (9.25 g; 50.0 mmoles) weredissolved in 70 ml of concentrated hydrochloric acid and heated at anoil bath temperature of 105°. After 64 hours of heating the mixture wasevaporated under reduced pressure and the residue triturated withacetone. The collected product was re-triturated with ethanol, filteredand dried to yield the title compound, mp 170°-200°.

Anal. Calcd for C₆ H₁₃ Cl₂ N₃ S₂ : C, 27.48; H, 4.90; N, 16.02; S,24.46; Cl, 27.04. Found: C, 27.29; H, 5.07; N, 15.91; S, 24.15; Cl,27.24.

B.3-{2-[(2-Aminothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(2-aminothiazol-4-yl)methylthio]ethylamine (from thedihydrochloride, 3.0 g; 11.4 mmoles) [prepared in Step A] in 25 ml ofmethanol as added dropwise over 1.5 hours to a cold (5°), stirred,partial suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.03g; 11.4 mmoles) in 55 ml of methanol. After 1.5 hours, anhydrousmethylamine was bubbled into the solution for 30 minutes and stirred at5° for 19 hours. The reaction mixture was evaporated under reducedpressure and the residue placed on 400 g of silica gel andchromatographed using acetone-methylene chloride (7:3). The appropriatefractions were combined and evaporated to give product.Recrystallization from 95% ethanol yielded the title compound, mp200°-201°.

Anal. Calcd for C₉ H₁₄ N₆ O₂ S₃ : C, 32.32; H, 4.32; N, 25.13; S, 28.76.Found: C, 32.25; H, 4.20; N, 25.06; S, 29.14.

EXAMPLE 1233-Amino-4-{2-[(2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A solution of2-[(2-dimethylaminomethylthiazol-5-yl)methylthio]ethylamine (2.05 g;8.86 mmoles) [prepared in Example 114, Step D] in 70 ml of methanol wasadded dropwise to a cold (8°), stirred, solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.44 g; 8.88 mmoles) in 170 mlof methanol. Anhydrous ammonia was bubbled into the solution for 8minutes and then stirred at ambient temperature for 0.5 hours. Thereaction mixture was evaporated under reduced pressure and the residuetriturated with acetonitrile to give 1.76 g of product. The product waspurified by flash chromatography on 100 g of silica gel (230-400 mesh)using acetonitrile-methanol. The appropriate fractions were combined,evaporated and the residue crystallized from acetone to yield the titlecompound, mp 131°-133°.

Anal. Calcd for C₁₁ H₁₇ N₆ OS₃ : C, 38.13; H, 5.24; N, 24.26; S, 27.76.Found (corr. for 0.49% H₂ O): C, 37.86; H, 5.06; N, 24.34; S, 27.68.

EXAMPLE 1243-Amino-4-{2-[(2-aminothiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A solution of 2-[(2-aminothiazol-4-yl)methylthio]ethylamine (from thedihydrochloride, 2.62 g; 10.0 mmoles) [prepared in Example 122, Step A]in 20 ml of methanol was added dropwise over 30 minutes to a cold (5°)solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.62 g; 10.0mmoles) in 50 ml of methanol. After stirring for 1.5 hours, anhydrousammonia was bubbled into the solution for 30 minutes and the solutionkept at 5° for 17 hours. The reaction mixture was evaporated underreduced pressure and the residue was chromatographed on a PreparativeHPLC system using μ-porasil silica gel. The appropriate fractions werecombined and evaporated under reduced pressure to give the titlecompound as an amorphous solid; the NMR spectrum (100 MHz) in d₆dimethyl sulfoxide showed the presence of approximately 0.4 moles ofethanol.

Anal. Calcd for C₈ H₁₂ N₆ OS₃ ·0.4C₂ H₆ O: C, 32.74; H, 4.50; N, 26.03;S, 29.80. Found (corr. for 1.39% H₂ O): C, 32.39; H, 4.28; N, 28.39; S,30.02.

EXAMPLE 1253-Methylamino-4-{2-[(2-{2,3-dimethylguanidino}thiazol-4-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

A solution of2-[(2-{2,3-dimethylguanidino}thiazol-4-yl)methylthio]ethylamine (2.5 g;9.64 mmoles) [prepared in Example 120, Step A] in methanol was addeddropwise over a period of 40 minutes to a cold (8°), stirred suspensionof 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1.72 g; 9.64 mmoles) in270 ml of methanol. Anhydrous methylamine was bubbled into the solutionfor 7 minutes and the solution then was evaporated under reducedpressure. The residue was chromatographed on 100 g of silica gel(230-400 mesh) by flash chromatography and the appropriate fractionswere combined and evaporated to give 2.5 g of product as a foam.Crystallization from aqueous ethanol yielded the title compound, mp132°-137°.

Anal. Calcd for C₁₂ H₂₀ N₈ O₂ S₃ : C, 35.63; H, 4.98; N, 27.70; S,23.78. Found (corr. for 4.78% H₂ O): C, 35.74; H, 5.04; N, 27.87; S,23.56.

EXAMPLE 1263-{2-[(2-Dimethylaminothiazol-4-yl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole1-oxide

A. 2-[(2-Dimethylaminothiazol-4-yl)methylthio]ethylamine

Cysteamine hydrochloride (5.24 g; 45.9 mmoles) and2-dimethylamino-4-chloromethylthiazole hydrochloride (9.8 g; 45.9mmoles) [prepared from N,N-dimethylthiourea and1,3-dichloro-2-propanone] were dissolved in 45 ml of concentratedhydrochloric acid and heated at an oil bath temperature of 100° for 96hours. The mixture was evaporated under reduced pressure and the residuemade basic with 40% aqueous NaOH. The aqueous phase was extracted withmethyl acetate, dried and evaporated to give the title compound as anoil which was used without further purification in Step B.

The NMR spectrum (60 MHz) in D₂ O gave the following resonances δ: 6.97(s, 1H); 3.94 (s, 2H); 3.67 (s, 3H); 3.15 (s, 3H); 3.05 (m, 4H).

B.3-{2-[(2-Dimethylaminothiazol-4-yl)methylthio]ethylamino}-4-amino-1,2,5-thiadiazole1-oxide

A solution of 2-[(2-dimethylaminothiazol-4-yl)methylthio]ethylamine (3.5g; 16.1 mmoles) [prepared in Step A] in 70 ml of methanol was addeddropwise over a period of 30 minutes to a cold (7°), stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.61 g; 16.1 mmoles) in 200 mlof methanol. Anhydrous ammonia was bubbled into the solution for 8minutes and after stirring for 30 minutes the mixture was evaporatedunder reduced pressure. The residue was triturated with isopropylalcohol then dissolved in methanol, filtered and evaporated to giveproduct. The product was purified by flash chromatography on 100 g ofsilica gel (230-400 mesh) using methylene chloride-methanol. Theappropriate fractions were combined and re-chromatographed by HPLC on aμ-porasil silica gel column. The appropriate fractions were combined andevaporated under reduced pressure to yield the title compound, mp116°-122°; the NMR spectrum (100 MHz) in d₆ dimethyl sulfoxide showedthe presence of approximately 1/3 mole of ethanol.

Anal. Calcd for C₁₀ H₁₆ N₆ OS₃.1/3 C₂ H₆ O: C, 36.83; H, 5.22; N, 24.16.Found (corr. for 11.92% H₂ O): C, 36.61; H, 4.06; N, 24.22.

EXAMPLE 1273-{2-[(2-Dimethylaminothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(2-dimethylaminothiazol-4-yl)methylthio]ethylamine (2.5g; 11.5 mmoles) [prepared in Example 126, Step A] was added dropwiseover a period of 30 minutes to a cold (7°), stirred suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (2.05 g; 11.5 mmoles) in 200ml of methanol. Anhydrous methylamine was bubbled into the solution for7 minutes and after stirring for 30 minutes, the mixture was evaporatedunder reduced pressure. The residue was crystallized from methanol togive 1.6 g of product. Two recrystallizations from 2-methoxyethanolyielded the title compound, mp 227°-229°.

EXAMPLE 1283-{2-[(2-{2-Imidazolidinyl}iminothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A. 2-[(2-{2-Imidazolidinyl}iminothiazol-4-yl)methylthio]ethylamine

Cysteamine hydrochloride (2.22 g; 19.5 mmoles) and2-[(2-imidazolidinyl)imino]-4-chloromethylthiazole hydrochloride (4.94g; 19.51 mmoles) [prepared from 1,3-dichloro-2-propanone andN-(2-imidazolidin-2-yl)thiourea which is itself prepared from2-(cyanimino)imidazolidine] were dissolved in 20 ml of concentratedhydrochloric acid and heated at an oil bath temperature of 100° for 5.5hours. The reaction mixture was evaporated under reduced pressure andthe residue made basic with 40% NaOH. The aqueous phase was extractedwith methyl acetate, dried and evaporated to give 2.02 g of the titlecompound which was used in the next step without further purification.

B.3-{2-[(2-{2-Imidazolidinyl}iminothiazol-4-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

A solution of2-[(2-{2-imidazolidinyl}iminothiazol-4-yl)methylthio]ethylamine (2.02 g;7.85 mmoles) [prepared in Step A] in 85 ml of methanol was addeddropwise over 40 minutes to a cold (8°), stirred suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1.4 g; 7.85 mmoles) in 190ml of methanol. Anhydrous methylamine was bubbled into the solution for7 minutes and, after 30 minutes at ambient temperature, the mixture wasevaporated under reduced pressure to give 3.5 g of product. The productwas chromatographed on a Preparative HPLC system using μ-porasil silicagel. The appropriate fractions were combined, evaporated and the residuecrystallized from methanol to give the title compound, mp 229°-231°.Recrystallization from aqueous ethanol gave the title compound with mp136°-140° which resolidified with remelting at mp 219°-224°.

Anal. Calcd for C₁₂ H₁₈ N₈ O₂ S₃ : C, 35.81; H, 4.51; N, 27.84; S,23.90. Found (corr. for 4.59% H₂ O): C, 35.51; H, 4.43; N, 27.98; S,23.56.

EXAMPLE 1293-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-[(2-pyridyl)methylamino]-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 65 was repeated except that themethylamine utilized therein was replaced by an equimolar amount of2-aminomethylpyridine. Column chromatography of the crude solid yielded3.08 g of product. Recrystallization from isopropyl alcohol yielded thetitle compound, mp 162°-164° (dec.).

Anal. Calcd for C₁₈ H₂₄ N₆ O₂ S₃ : C, 47.76; H, 5.34; N, 18.57. Found:C, 47.80; H, 5.32; N. 18.75.

EXAMPLE 1303-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-[(4-pyridyl)methylamino]-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 65 was repeated except that themethylamine utilized therein was replaced by an equimolar amount of4-aminomethylpyridine. After chromatography the crude product wasdissolved in hot isopropyl alcohol, decanted from insoluble material andthe solution treated with anhydrous HCl to give the title compound asthe hydrochloride salt. This salt was dissolved in water and madealkaline with saturated aqueous sodium bicarbonate solution to give,after filtration, the title compound as a free base, mp 88°-90°.

Anal. Calcd. for C₁₈ H₂₄ N₆ O₂ S₃ : C, 47.76; H, 5.34; N, 18.57. Found(corr. for 3.73% H₂ O): C, 47.54; H, 5.32; N, 19.09.

EXAMPLE 1313-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-ethylamino-1,2,5-thiadiazole1,1-dioxide

The general procedure of Example 65 was repeated except that themethylamine utilized therein was replaced by an equimolar amount ofethylamine. The appropriate fractions from column chromatography weredissolved in warm isopropyl alcohol and saturated with anhydrous HCl.The crystalline solid was collected by filtration, washed with acetoneand dried to give 2.9 g of the title compound as its hydrochloride salt,mp 246°-247° (dec.).

Anal. Calcd for C₁₄ H₂₄ ClN₅ O₂ S₃ : C, 39.47; H, 5.68; N, 16.44; Cl,8.32. Found: C, 39.81; H, 5.74; N, 16.62; Cl, 8.20.

EXAMPLE 1323-Methylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide

A solution of 3-(3-piperidinomethylphenoxy)propylamine (2.35 g; 9.45mmoles) [prepared according to published U.K. patent application No.2,023,133] in 30 ml of methanol was added dropwise over a period of 40minutes to a stirred partial suspension of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1.68 g; 9.45 mmoles) thathad been cooled to 1° in an ice-water bath. After 15 minutes, anhydrousmethylamine was bubbled into the solution for 5 minutes and the solutionthen was stirred at ambient temperature for 30 minutes. The reactionmixture was evaporated under reduced pressure and the residuechromatographed by flash chromatography on 100 g of silica gel (230-400mesh) using methanol-acetonitrile. The appropriate fractions werecombined and evaporated to give 2.2 g of product. Recrystallization fromacetonitrile with charcoal treatment yielded the title compound, mp182°-184°.

Anal. Calcd for C₁₈ H₂₇ N₅ O₃ S: C, 54.94; H, 6.92; N, 17.80; S, 8.15.Found: C, 54.90; H, 7.07; N, 18.14; S, 8.29.

EXAMPLE 1333-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide

A solution of 3-(3-piperidinomethylphenoxy)propylamine (from thedihydrochloride, 4.0 g; 12.4 mmoles) in 40 ml of methanol was addeddropwise over a period of 50 minutes to a solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.01 g; 12.4 mmoles) in 200 mlof methanol that had been cooled to 0° in an ice-water bath. After 15minutes, anhydrous ammonia was bubbled into the solution for 5 minutesand the solution then was stirred at ambient temperature for 17 hours.The reaction mixture was evaporated under reduced pressure and theresidue chromatographed by flash chromatography on 100 g of silica gel(230-400 mesh) using methanol-acetonitrile. The appropriate fractionswere combined and evaporated to give 4.18 g of product.Recrystallization from 95% aqueous ethanol yielded the title compound,mp 155°-157° (dec.).

Anal. Calcd for C₁₇ H₂₅ N₅ O₂ S: C, 56.17; H, 6.93; N, 19.27; S, 8.82.Found: C, 55.97; H, 7.04; N, 19.57; S, 8.63.

EXAMPLE 1343-Amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide

A solution of 3-(3-piperidinomethylphenoxy)propylamine (from thedihydrochloride, 4.0 g; 12.4 mmoles) in 35 ml of methanol was addeddropwise over a period of 65 minutes to a stirred partial suspension of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (2.22 g; 12.4 mmoles) in 200 mlof methanol that had been cooled to 2° in an ice-water bath. After 15minutes anhydrous ammonia was bubbled into the solution for 5 minutesand the solution then was stirred at ambient temperature for 30 minutes.The reaction mixture was evaporated under reduced pressure and theresidue placed on 100 g of silica gel (230-400 mesh) and chromatographedby flash chromatography using methanol-acetonitrile. The appropriatefractions were combined and evaporated to give 3.2 g of product. The NMRspectrum (100 MHz) in d₆ dimethyl sulfoxide showed the followingresonances δ: 7.2 (m, 1H); 6.9 (m, 3H); 4.1 (t, 2H); 3.5 (t, 2H); 3.4(s, 2H); 2.3 (m, 4H); 2.0 (m, 2H); 1.4 (broad s, 6H).

EXAMPLE 135 3-{2-[(5-Dimethylaminomethyl-2-thienyl)methylthio]ethylamino}-4-(3,4-methylenedioxybenzylamino)-1,2,5-thiadiazole1,1-dioxide

A solution of 2-[(5-dimethylaminomethyl-2-thienyl)methylthio]ethylamine(2.02 g; 8.8 mmoles) in 30 ml of methanol was added dropwise over aperiod of 40 minutes to a stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide (1.56 g; 8.8 mmoles) in 200ml of methanol that had been cooled to 0° in an ice-water bath. After 20minutes, piperonylamine (1.46 g; 9.6 mmoles) was added and the mixturestirred at ambient temperature for 3 hours. The reaction mixture wasevaporated to near dryness, ether was added, and the mixture wasfiltered to give 3.47 g of product. Recrystallization from methanolyielded the title compound, mp 180°-182°.

Anal. Calcd for C₂₀ H₂₅ N₅ O₄ S₃ : C, 48.46; H, 5.08; N, 14.13. Found(corr. for 0.38% H₂ O): C, 48.92; H, 4.88; N, 14.52.

EXAMPLE 1363-Amino-4-{2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A. 6-(N,N-dimethylcarbamyl)-2-carbomethoxypyridine

A solution of 6-carbomethoxy-2-picolinic acid (22.8 g; 0.13 mole) in 80ml of thionyl chloride was heated at an oil bath temperature of 100° for3 hours. The solution was evaporated under reduced pressure and theresidue dissolved in 200 ml of dioxane which then was added dropwise toa solution of dimethylamine (70 g) in dioxane. The reaction mixture wasstirred for 2 hours and then allowed to stand at 4° overnight, filteredand evaporated under reduced pressure. The residue was dissolved intoluene, diluted with methylcyclohexane and filtered to give 20.7 g ofthe title compound, mp 90°-92°.

Anal. Calcd for C₁₀ H₁₂ N₂ O₃ : C, 57.68; H, 5.81; N, 13.46. Found: C,57.64; H, 5.85; N, 13.77.

B. 6-Dimethylaminomethyl-2-hydroxymethylpyridine

A solution of 6-(N,N-dimethylcarbamyl-2-carbomethoxypyridine (20.3 g;97.5 mmoles) [prepared in Step A] in 200 ml of tetrahydrofuran was addedto a suspension of lithium aluminum hydride (9.6 g; 0.25 moles) in 500ml of tetrahydrofuran. The mixture was stirred and heated at refluxtemperature under a nitrogen atmosphere for 3 hours then left at ambienttemperature overnight. The mixture was decomposed with a saturatedaqueous solution of Na₂ SO₄, filtered, dried and evaporated underreduced pressure. The residue was placed on 275 g of aluminum oxide andeluted with methylene chloride. The appropriate fractions were combinedand evaporated to give 5.2 g of the title compound.

The NMR spectrum (60 MHz) in CDCl₃ gave the following resonances δ: 7.38(m, 3H); 4.75 (s, 2H); 3.58 (s, 2H); 2.27 (s, 6H).

C. 2-[(6-Dimethylaminomethyl-2-pyridyl)methylthio]ethylamine

Cysteamine hydrochloride (3.58 g; 31.5 mmoles) and6-dimethylaminomethyl-2-hydroxymethylpyridine (5.0 g; 30.1 mmole)[prepared in Step B] were dissolved in 50 ml of 48% hydrobromic acid andthe solution heated at reflux temperature for 12 hours and then allowedto stand at ambient temperature for 8 hours. The reaction mixture wasevaporated under reduced pressure to half volume, made basic with 40%aqueous NaOH and extracted with several portions of methylene chloride.The combined organic phase was washed with a small amount of water andsaturated brine solution then dried and evaporated under reducedpressure to yield 3.14 g of the title compound.

The NMR spectrum (60 MHz) in CDCl₃ gave the following resonances δ: 7.5(m, 3H); 3.83 (s, 2H); 3.56 (s, 2H); 2.7 (m, 4H); 2.28 (s, 6H).

D.3-Amino-4-{2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide issuccessively treated with an equimolar amount of2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethyalmine [prepared inStep C] and excess ammonia, the title compound is thereby produced.

EXAMPLE 1373-Amino-4-{2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is successively treated with an equimolar amount of2-[(6-dimethylaminomethyl-2-pyridyl)methylthio]ethylamine [prepared inExample 136, Step C] and excess ammonia, the title compound is therebyproduced.

EXAMPLE 1383-{2-[(5-Guanidino-1,2,4-thiadiazol-3-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is successively treated with an equimolar amount of2-[(5-guanidino-1,2,4-thiadiazol-3-yl)methylthio]ethylamine [preparedaccording to the procedure described in published European PatentApplication No. 6679] and excess methylamine, the title compound isthereby produced.

EXAMPLE 1393-Amino-4-{2-[(5-guanidino-1,2,4-thiadiazol-3-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole,1,1-dioxide is successively treated with an equimolar amount of2-[(5-guanidino-1,2,4-thiadiazol-3-yl)methylthio]ethylamine and excessammonia, the title compound is thereby produced.

EXAMPLE 1403-Amino-4-{2-[(5-guanidino-1,2,4-thiadiazol-3-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide issuccessively treated with an equimolar amount of2-[(5-guanidino-1,2,4-thiadiazol-3-yl)methylthio]ethylamine and excessammonia, the title compound is thereby produced.

EXAMPLE 1413-{2-[(5-Guanidino-1,2,4-oxadiazol-3-yl)methylthio]ethylamino}-4-methylamino-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is successively treated with an equimolar amount of2-[(5-guanidino-1,2,4-oxadiazol-3-yl)methylthio]ethylamine [preparedaccording to the procedure described in published European PatentApplication No. 6286] and excess methylamine, the title compound isthereby produced.

EXAMPLE 1423-Amino-4-{2-[(5-guanidino-1,2,4-oxadiazol-3-yl)methylthio]ethylamino}-1,2,5-thiadiazole1,1-dioxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole1,1-dioxide is successively treated with an equimolar amount of2-[(5-guanidino-1,2,4-oxadiazol-3-yl)methylthio]ethylamine and excessammonia, the title compound is thereby produced.

EXAMPLE 1433-Amino-4-{2-[(5-guanidino-1,2,4-oxadiazol-3-yl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide issuccessively treated with an equimolar amount of2-[(5-guanidino-1,2,4-oxadiazol-3-yl)methylthio]ethylamine and excessammonia, the title compound is thereby produced.

EXAMPLE 144

The general procedure of Example 132 is repeated, except that the3-(3-piperidinomethylphenoxy)propylamine utilized therein is replaced byan equimolar amount of

(a) 3-(3-pyrrolidinomethylphenoxy)propylamine,

(b) 3-[3-(4-methylpiperidino)methylphenoxy]propylamine,

(c) 3-(3-homopiperidinomethylphenoxy)propylamine,

(d) 3-(3-morpholinomethylphenoxy)propylamine¹ and

(e) 3-[3-(N-methylpiperazino)methylphenoxy]propylamine², respectively,and there is thereby produced

(a)3-Methylamino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide, mp 156°-157° C.,

(b)3-Methylamino-4-{3-[3-(4-methylpiperidino)methylphenoxy]propylamino}-1,2,5-thiadiazole1,1-dioxide, mp 186°-189° C.,

(c)3-Methylamino-4-[3-(3-homopiperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide, mp 174°-176° C. as the hydrochloride,

(d)3-Methylamino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide, mp 162°-163° C., and

(e)3-Methylamino-4-{3-[3-(N-methylpiperazino)methylphenoxy]propylamino}-1,2,5-thiadiazole1,1-dioxide, respectively.

The above starting materials (1) and (2) are prepared by hydrogenationof a mixture of N-[3-(3-formylphenoxy)propyl]phthalimide and thecorresponding morpholine or N-methylpiperazine over 10% palladium/carboncatalyst and then removal of the phthalimido protecting group withhydrazine. The other starting materials are prepared according to theprocedures described in published U.K. Patent Application No. 2,023,133.

EXAMPLE 145

The general procedure of Example 133 is repeated, except that the3-(3-piperidinomethylphenoxy)propylamine utilized therein is replaced byan equimolar amount of

(a) 3-(3-pyrrolidinomethylphenoxy)propylamine,

(b) 3-[3-(4-methylpiperidino)methylphenoxy]propylamine,

(c) 3-(3-homopiperidinomethylphenoxy)propylamine,

(d) 3-[3-(heptamethyleneiminomethyl)phenoxy]propylamine,

(e) 3-(3-morpholinomethylphenoxy)propylamine and

(f) 3-[3-(N-methylpiperazino)methylphenoxy]propylamine, respectively,and there is thereby produced

(a)3-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide, mp 168°-170° C. (dec.)

(b)3-Amino-4-{3-[3-(4-methylpiperidino)methylphenoxy]propylamino}-1,2,5-thiadiazole1-oxide, mp 157°-159° C.,

(c)3-Amino-4-[3-(3-homopiperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide, mp 167°-169° C.,

(d)3-Amino-4-{3-[3-(heptamethyleneiminomethyl)phenoxy]propylamino}-1,2,5-thiadiazole1-oxide, mp 154°-157° C.,

(e)3-Amino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide and

(f)3-Amino-4-{3-[3-(N-methylpiperazino)methylphenoxy]propylamino}-1,2,5-thiadiazole1-oxide, respectively.

EXAMPLE 146

The general procedure of Example 134 is repeated, except that the3-(3-(piperidinomethylphenoxy)propylamine utilized therein is replacedby an equimolar amount of

(a) 3-(3-pyrrolidinomethylphenoxy)propylamine,

(b) 3-[3-(4-methylpiperidino)methylphenoxy]propylamine,

(c) 3-(3-homopiperidinomethylphenoxy)propylamine,

(d) 3-(3-morpholinomethylphenoxy)propylamine and

(e) 3-[3-(N-methylpiperazino)methylphenoxy]propylamine, respectively,and there is thereby produced

(a)3-Amino-4-[3-(3-pyrrolidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide, mp 160°-163° C. (dec.)

(b)3-Amino-4-{3-[3-(4-methylpiperidino)methylphenoxy]propylamino}-1,2,5-thiadiazole1,1-dioxide,

(c)3-Amino-4-[3-(3-homopiperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

(d)3-Amino-4-[3-(3-morpholinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide, mp 172°-174° C. (dec.), and

(e)3-Amino-4-{3-[3-(N-methylpiperazino)methylphenoxy]propylamino}-1,2,5-thiadiazole1,1-dioxide, respectively.

EXAMPLE 147

The general procedure of Example 132 is repeated, except that themethylamine utilized therein is replaced by an equimolar amount of

ethylamine,

propylamine,

n-butylamine,

allylamine,

2-propynylamine,

cyclopropylamine,

aminomethylcyclopropane,

ethanolamine,

2-methoxyethylamine,

2,2,2-trifluoroethylamine,

2-fluoroethylamine,

hydroxyamine,

3-aminopropionitrile

benzylamine,

3-methoxybenzylamine,

4-methoxybenzylamine,

3,4-dimethoxybenzylamine,

piperonylamine,

4-chlorobenzylamine,

2-aminomethylpyridine,

3-aminomethylpyridine and

4-aminomethylpyridine, respectively, and there is thereby produced

3-Ethylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-Propylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-Butylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-Allylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(2-Propynyl)amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(Cyclopropylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-[(Cyclopropyl)methylamino]-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(2-Hydroxyethylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(2-Methoxyethylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(2,2,2-trifluoroethylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(2-Fluoroethylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-Hydroxyamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(3-Cyanopropylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-Benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(3-Methoxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(4-Methoxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(3,4-Dimethoxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(3,4-Methylenedioxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-(4-Chlorobenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-[(2-Pyridyl)methylamino]-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide,

3-[(3-Pyridyl)methylamino]-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide, and

3-[(4-Pyridyl)methylamino]-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1,1-dioxide, respectively.

EXAMPLE 148

The general procedures of Example 147 are repeated except that the3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide utilized therein is replacedby an equimolar amount of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide, andthere are thereby produced

3-Ethylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-Propylamino-4-83-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide,

3-Butylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-Allylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(2-Propynyl)amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(Cyclopropylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-[(Cyclopropyl)methylamino]-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(2-Hydroxyethylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(2-Methoxyethylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(2,2,2-Trifluoroethylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(2-Fluoroethylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-Hydroxyamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(3-Cyanopropylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-Benzylamino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(3-Methoxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(4-Methoxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(3,4-Dimethoxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(3,4-Methylenedioxybenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-(4-Chlorobenzylamino)-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide,

3-[(2-Pyridyl)methylamino]-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide

3-[(3-Pyridyl)methylamino]-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide, mp 139.5°-143° C., and

3-[(4-Pyridyl)methylamino]-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide, respectively.

EXAMPLE 1493-[(3-Pyridyl)methylamino]-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole1-oxide

A solution of 3-(3-piperidinomethylphenoxy)propylamine (from thedihydrochloride, 3.21 g; 10.0 mmoles) in 30 ml of methanol was addeddropwise over a period of 60 minutes to a partial solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (1.62 g; 10.0 mmoles) that hadbeen cooled to 5°-7° in an ice-water bath. After 3 hours at ambienttemperature, a solution of 3-aminomethylpyridine (1.14 g; 10.5 mmoles)in 10 ml of methanol was added and the solution was then stirred for 18hours. The reaction mixture was evaporated under reduced pressure andthe residue chromatographed by flash chromatography on 100 g of silicagel (230-400 mesh) using methylene chloride-methanol-ammonia. Theappropriate fractions were combined, evaporated and triturated withacetonitrile to give 4.05 g of product. Recrystallization from isopropylalcohol yielded the title compound, mp 139.5°-143°.

Anal. Calc'd. for C₂₃ H₃₀ N₆ O₂ S: C, 60.77; H, 6.65; L N, 18.49; S,7.04. Found: C, 60.66; H, 6.64; N, 18.22; S, 7.02.

EXAMPLE 1503-Amino-4-[3-(3-guanidinophenoxy)propylamino]-1,2,5-thiadiazole 1-oxide

A. N-[3-(3-Nitrophenoxy)propyl]phthalimide

A partial suspension of m-nitrophenol (6.0 g; 43.0 mmoles),N-(3-bromopropyl)phthalimide (10.0 g; 37.0 mmoles) and potassiumcarbonate (8.0 g; 58.0 mmoles) in 50 ml of DMF was stirred at ambienttemperature for 70 hours. The reaction mixture was diluted with 80 ml ofwater and filtered to give product. Recrystallization from2-methoxyethanol yielded 9.15 g of the title compound, mp 149°-152°.

Anal. Calc'd. for C₁₇ H₁₄ N₂ O₅ : C, 62.57; H, 4.32; N, 8.59. Found: C,62.49; H, 4.30; N, 8.71.

B. N-[3-(3-Aminophenoxy)propyl]phthalimide

A suspension of N-[3-(3-nitrophenoxy)propyl]phthalimide (1.0 g; 3.1mmoles) [prepared in Step A] and 10% palladium on carbon (0.2 g) in 100ml of 2-methoxyethanol was hydrogenated in a Parr Apparatus at ambienttemperature for 45 minutes. The reaction mixture was filtered and thefiltrate was evaporated to dryness to give 0.91 g of crude product.

An analytical sample was prepared by flash chromatography on silica gelusing methylene chloride-methanol and recrystallization from absoluteethanol yielded the title compound, mp 157°-162°.

Anal. Calc'd. for C₁₇ H₁₆ N₂ O₃ : C, 68.91; H, 5.44; N, 9.45. Found: C,69.00; H, 5.54; N, 9.52.

C. N-[3-(3-Guanidinophenoxy)propyl]phthalimide

A mixture of crude N-[3-(3-aminophenoxy)propyl]phthalimide (13.27 g;45.0 mmoles) [prepared in Step B], 50% aqueous cyanamide (7.9 ml) and 12N hydrochloric acid (3.78 ml; 45.0 mmoles) in 39.4 ml of absoluteethanol was heated at reflux for 21/4 hours. An additional 7.9 ml of 50%aqueous cyanamide was added and heating was continued for 15 hours. Thereaction mixture was evaporated under reduced pressure and the residuechromatographed by flash chromatography on 120 g of silica gel (230-400mesh) using methylene chloride-methanol. The appropriate fractions werecombined, evaporated and triturated with cold acetonitrile to give 5.85g of product. Recrystallization from absolute ethanol yielded the titlecompound as a hydrochloride salt, mp 185°-187°.

Anal. Calc'd. for C₁₈ H₁₈ N₄ O₃.HCl: C, 57.68; H, 5.11; N. 14.95; Cl,9.46. Found: C, 57.65; H, 5.55; N, 15.08; Cl, 9.16.

D. 3-(3-Guanidinophenoxy)propylamine

To a partial suspension of N-[3-(3-guanidinophenoxy)propyl]phthalimidehydrochloride (1.0 g; 2.95 mmoles) in 10 ml of 95% aqueous ethanol wasadded 0.27 ml of hydrazine hydrate. The mixture was stirred at ambienttemperature for 17 hours and evaporated under reduced pressure to givethe title compound. The product was used without further purification inStep E.

E. 3-Amino-4-[3-(3-guanidinophenoxy)propylamino]-1,2,5-thiadiazole1-oxide

To a solution of crude 3-(3-guanidinophenoxy)propylamine [prepared inStep D] in 10 ml of methanol was added3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (0.59 g; 4.0 mmoles) and themixture was stirred at ambient temperature for 17 hours and then heatedat 50° for 2.5 hours. The reaction mixture was filtered, evaporatedunder reduced pressure and the residue was chromatographed by flashchromatography on 75 g of silica gel (230-400 mesh) usingmethanol-methylene chloride. The appropriate fractions were combined andevaporated under reduced pressure to yield 0.25 g of the title compoundas an oil; TLC [silica gel/CH₂ Cl₂ :CH₃ OH (4:1)] gave Rf=0.21.

The NMR spectrum (60 MHz) in d₆ dimethyl sulfoxide gave the followingresonances δ: 9.33 (s, 1H); 8.43 (s, 2H); 7.52 (m, 4H); 7.43 (m, 1H);6.83 (m, 3H); 4.13 (broad t, 2H); 3.51 (broad t, 2H); 2.10 (broad t,2H).

EXAMPLE 1513-Amino-4-{2-[(5-piperidinomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A. 3-Amino-4-methoxy-1,2,5-thiadiazole 1-oxide

A 2.75 N solution of ammonia (56.0 ml; 0.154 mmole) in methanol wasadded dropwise over 1 hour to a well-stirred solution of3,4-dimethoxy-1,2,5-thiadiazole 1-oxide (24.3 g; 0.15 mole) in 725 ml ofmethanol at 20°. The resultant solution was stirred at ambienttemperature for 3 hours and then was concentrated to about 125 ml atreduced pressure. After 16 hours at 0°, the mixture was filtered anddried to give 19.9 g of product.

An analytical sample was prepared by recrystallization from methanol toyield the title compound, mp 182°-184° (dec.)

Anal. Calc'd. for C₃ H₅ N₃ O₂ S: C, 24.49; H, 3.43; N, 28.56; S, 21.79.Found: C, 24.22; H, 3.63; N, 28.60; S, 21.92.

B.3-Amino-4-{2-[(5-piperidinomethyl-2-furyl)methylthio]ethylamino}-1,2,5-thiadiazole1-oxide

A solution of 2-[(5-piperidinomethyl-2-furyl)methylthio]ethylamine (4.0g; 15.7 mmoles) [prepared according to the procedure described inBelgian Patent No. 857,388 (U.S. Pat. No. 4,128,658)] in 25 ml ofmethanol was added all at once to a stirred suspension of3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide (2.31 g; 15.7 mmoles)[prepared in Step A] in 25 ml of methanol at ambient temperature. Afterstirring for 16 hours, the solution was evaporated under reducedpressure and the residue chromatographed by flash chromatography on 100g of silica gel (230-400 mesh) using methanol-acetonitrile. Theappropriate fractions were combined and evaporated to give 3.71 g ofproduct. Recrystallization from 95% aqueous ethanol with charcoaltreatment yielded the title compound, mp 161°-163°.

Anal. Calc'd. for C₁₅ H₂₃ N₅ O₂ S₂ : C, 48.76; H, 6.27; N, 18.96; S,17.36. Found: c, 48.86; H, 6.16; N, 19.66; S, 17.63.

I claim:
 1. A compound of the formula ##STR60## wherein p is 1 or 2; R⁷ is a leaving group selected from halogen, (lower)alkoxy, (lower)alkylthio, phenoxy, phenylthio, substituted phenoxy and substituted phenylthio wherein the phenyl ring may contain 1 or 2 substituents selected from halogen, (lower)alkyl, (lower)alkoxy and nitro; andR¹² is A(CH₂)_(m) Z(CH₂)_(n) NH--, R² R³ N-- or HS(CH₂)_(n) NH--; in which R² and R³ each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cyclo(lower)alkyl(lower)alkyl, hydroxy(lower)alkyl, (lower)alkoxy(lower)alkyl, (lower)alkylthio(lower)alkyl, 2-fluoroethyl, 2,2,2-trifluoroethyl or cyano(lower)alkyl, or, when R² is hydrogen, R³ may also be cyclo(lower)alkyl, amino(lower)alkyl, (lower)alkylamino(lower)alkyl, di(lower)alkylamino(lower)alkyl, pyrrolidino(lower)alkyl, piperidino(lower)alkyl, piperazino(lower)alkyl, substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, amino, (lower)alkylamino, di(lower)alkylamino, hydroxy, (lower)alkoxy, 2,3-dihydroxypropyl, cyano, amidino, (lower)alkylamidino, phenyl, phenyl(lower)alkyl, substituted phenyl or substituted phenyl(lower)alkyl, wherein the phenyl ring may contain one or two substituents independently selected from (lower)alkyl, hydroxy, (lower)alkoxy and halogen or one substituent selected from methylenedioxy, trifluoromethyl and di(lower)alkylamino; or R² and R³, taken together, may be --CH₂ CH₂ X(CH₂)_(r) --; r is an integer of from 1 to 3, inclusive; X is methylene, sulfur, oxygen or N--R⁴, provided that, when p is 2 and R⁷ is methoxy, R² and R³ taken together with the nitrogen to which they are attached, may not be morpholino, and that, when r is 1, X is methylene; R⁴ is hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkanoyl or benzoyl; m is an integer of from zero to 2, inclusive; n is an integer of from 2 to 4, inclusive; Z is sulfur, oxygen or methylene; A is phenyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, furyl, thienyl or pyridyl; provided that A may contain one or two substituents, the first substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl, (lower)alkoxy, ##STR61## and the second substituent being selected from (lower)alkyl, hydroxy, trifluoromethyl, halogen, amino, hydroxymethyl and (lower)alkoxy; q is an integer of from 0 to 6, inclusive; R¹⁴ and R¹⁵ independently are hydrogen or (lower)alkyl, or if R¹⁴ is hydrogen, R¹⁵ also may be (lower)alkanoyl or benzoyl, or R¹⁴ and R¹⁵, taken together, may be ethylene; and R⁵ and R⁶ each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkoxy(lower)alkyl, cyclo(lower)alkyl or phenyl, provided that R⁵ and R⁶ may not both be cyclo(lower)alkyl or phenyl; or R⁵ and R⁶, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, homopiperidino, heptamethyleneimino or octamethyleneimino; or a salt, hydrate, solvate or N-oxide thereof.
 2. A compound of claim 1 wherein R¹² is A(CH₂)_(m) Z(CH₂)_(n) NH-- in which A is phenyl, imidazolyl, thiazolyl, furyl, thienyl or pyridyl, each of which may contain one or two substituents, the first substituent being selected from (lower)alkyl, ##STR62## and the second substituent being selected from (lower)alkyl; Z is sulfur, oxygen or methylene; m is zero or one; n is two or three; R¹⁴ and R¹⁵ independently are hydrogen or (lower)alkyl, or R¹⁴ and R¹⁵, taken together, may be ethylene; R⁵ and R⁶ each are independently hydrogen or (lower)alkyl; or R⁵ and R⁶, taken together with the nitrogen atom to which they are attached, may be pyrrolidino, methylpyrrolidino, dimethylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, hydroxypiperidino, homopiperidino, heptamethyleneimino or octamethyleneimino; and R⁷ is (lower)alkoxy.
 3. A compound of claim 1 wherein R¹² is ##STR63## in which Z is sulfur or methylene, R¹⁶ is methyl and R¹³ is hydrogen or methyl, or R¹⁶ and R¹³, taken together with the nitrogen atom to which they are attached, may be piperidino; and R⁷ is (lower)alkoxy.
 4. A compound of claim 3 wherein R⁷ is methoxy.
 5. A compound of claim 1 wherein R¹² is ##STR64## in which Z is sulfur or methylene; R¹⁴ and R¹⁵ independently are hydrogen or methyl, or R¹⁴ and R¹⁵, taken together, may be ethylene; and R⁷ is (lower)alkoxy.
 6. A compound of claim 5 wherein R⁷ is methoxy.
 7. A compound of claim 1 wherein R¹² is ##STR65## in which R¹³ is hydrogen or methyl; Z is sulfur or methylene; and R⁷ is (lower)alkoxy.
 8. A compound of claim 7 wherein R⁷ is methoxy.
 9. A compound of claim 1 wherein R¹² is ##STR66## in which R¹³ is hydrogen or methyl; Z is sulfur or methylene; and R⁷ is (lower)alkoxy.
 10. A compound of claim 9 wherein R⁷ is methoxy.
 11. A compound of claim 1 wherein R¹² is ##STR67## in which R⁵ and R⁶ each are independently hydrogen or (lower)alkyl, or, R⁵ and R⁶, taken together with the nitrogen atom to which they are attached, may be piperidino; Z is sulfur or methylene; and R⁷ is (lower)alkoxy.
 12. A compound of claim 11 wherein R⁷ is methoxy.
 13. A compound of claim 1 wherein R¹² is ##STR68## in which Z is oxygen or sulfur; R⁵ and R⁶ each are independently hydrogen or (lower)alkyl, or when R⁵ is hydrogen, R⁶ also may be (lower)alkenyl or (lower)alkynyl; or R⁵ and R⁶, taken together with the nitrogen to which they are attached, may be pyrrolidino, methylpyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, homopiperidino or heptamethyleneimino; and R⁷ is (lower)alkoxy.
 14. A compound of claim 13 wherein R⁷ is methoxy.
 15. A compound of claim 14 wherein R⁵ and R⁶ each are independently hydrogen or (lower)alkyl.
 16. A compound of claim 14 wherein R⁵ and R⁶, taken together with the nitrogen to which they are attached, represent piperidino.
 17. A compound of claim 1 wherein R¹² is ##STR69## in which Z is oxygen or sulfur; and R⁷ is (lower)alkoxy.
 18. A compound of claim 17 wherein R⁷ is methoxy.
 19. A compound of claim 1 wherein R¹² is R² R³ N-- in which R² and R³ each are independently hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl or cyclo(lower)alkyl(lower)alkyl, or, when R² is hydrogen, R³ also may be substituted pyridyl(lower)alkyl wherein the pyridyl ring may contain one substituent selected from (lower)alkyl, (lower)alkoxy, hydroxy, amino and halogen, phenyl(lower)alkyl or 3,4-methylenedioxybenzyl; and R⁷ is (lower)alkoxy.
 20. A compound of claim 19 wherein R⁷ is methoxy.
 21. The compound of claim 20 which is 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide.
 22. A compound of claim 1 wherein R¹² is HS(CH₂)_(n) NH-- in which n is an integer of from two to four; and R⁷ is (lower)alkoxy.
 23. A compound of claim 22 wherein R⁷ is methoxy. 